Phenanthroline-7-one derivatives and their therapeutic uses

ABSTRACT

A pharmaceutical composition including an efficient amount of a compound selected among the compounds of formulae (I) and (Ia). The compounds have interesting cytotoxic properties leading to a therapeutic use as antitumoral medicines.

The present invention relates to pharmaceutical compositions based on polyaromatic compounds of use in particular as antitumour medicaments.

In 1999, cytotoxic treatments (chemotherapy) used to reduce the size of cancerous tumours, to suppress the development of the tumour process or indeed even, in still too few cases, to eliminate clumps of cancer cells and the risk of metastases, combine chemical substances which have been recently introduced with to others which have been used for several decades. For example, 5-fluorouracil (5-FU), recognized for nearly 40 years as one of the most active treatments for colorectal cancer, can be replaced by one or other of the specific inhibitors of topoisomerase I (irinotecan or topotecan) when the tumour is no longer sensitive to 5-FU. More generally, the therapeutic arsenal available for treating colorectal tumours will also be enriched with the availability of oxaliplatin, novel in situ “donors” of 5-FU or selective inhibitors of thymidylate synthetase. This coexistence is not limited to the treatment of colorectal cancers since, in addition, the chemotherapy of breast, ovarian and lung cancers now makes wide use of the family of taxane derivatives (paclitaxel, docetaxel). The need for more effective and better tolerated treatments, thus improving the survival and the quality of life of the patients, is imperative since, still taking the example of colorectal tumours, it has been estimated (S. L. Parker, T. Tong, S. Bolden et al., CA Cancer J. Clin., 1997) that, in the United States alone, over 131 000 new cases were diagnosed in 1997, 54 000 of which were responsible for the death of the patient. It is the awareness of this situation which has prompted the inventors to focus their attention on a family of polyaromatic compounds which have not yet been studied to any great extent, identified in the Ascidia of warm seas, in order to develop a novel medicinal chemistry intended to select synthetic compounds resulting from chemical design/modulation research which possess a significant cytotoxic activity at the therapeutic level.

The seas and oceans which cover more than 70% of the surface of the planet harbour marine plants and sponges, which living species, under gradual systematic pharmacognosic, have been shown to be able to contain complex alkaloids exhibiting advantageous pharmacological properties. For example, the sponges Cryptotheca crypta and Halichondria okadai have formed the subject of in-depth studies since the discovery of the presence, in their cells, of cytarabine or of halichondrin B. It is the same for the tunicates, since the isolation of aplidine from the tunicate Aplidium albicans, which lives in the Balearic Islands (Spain). Alkaloids with a tetrahydroisoquinolone structure have been isolated from the ascidian Ecteinascidia turbinata. Among these, ecteinascidin-743 has formed the subject of in-depth preclinical studies (E. Igbicka et al., NCI-EORTC symposium, 1998; Abst. 130, p. 34) and of clinical trials intended to define its therapeutic potential as anticancer medicament (A. Bowman et al., NCI-EORTC symposium, 1998; Abst. 452, p. 118; M. Villanova-Calero et al., NCI-EORTC symposium, 1998; Abst. 453, p. 118; M. J. X. Hillebrand et al., NCI-EORTC symposium; 1998; Abst. 455, p. 119; E. Citkovic et al., NCI-EORTC symposium, 1998; Abst. 456, p. 119). Novel pentacyclic acridine derivatives have also formed the subject of pharmacochemical studies (D. J. Hagan et al., J. Chem. Soc., Perkin Transf., 1997; 1: 2739-2746).

Other natural alkaloid of marine origin, ascididemin, has been extracted from the tunicate Didemnum sp. (J. Kobayashi et al., Tetrahedron Lett., 1988; 29: 1177-80) and from the ascidian Cystodytes dellechiajei (I. Bonnard et al., Anti-cancer Drug Design, 1995; 10: 333-46). Ascididemin has antiproliferative properties demonstrated on the model of murine leukaemia (P388 or L1210 lines) and described by F. J. Schmitz et al. (J. Org. Chem. 1991; 56: 804-8), B. Lindsay et al. (Bioorg. Med. Chem. Lett., 1995; 5: 739-42) and J. Kobayashi et al. (Tetrahedron Lett., 1988; 29: 1177-80), and on the model of human leukaemia as described by I. Bonnard et al. (Anti-cancer Drug Design, 1995; 10: 333-46). Mention may also be made of 2-bromoleptoclinidone, isolated from the ascidian Leptoclinides sp. by S. J. Bloor et al. (J. Am. Chem. Soc., 1987; 109: 6134-6) and synthesized by F. Bracher et al. (Heterocycles, 1989; 29: 2093-95) and then by M. E. Jung et al. (Heterocycles, 1994; 39; 2: 767-778). 2-Bromoleptoclinidone exhibits cytotoxicity with respect to the leukaemia cell model with an ED₅₀ of 0.4 μg/ml. The cytotoxic properties were confirmed by F. Bracher (Pharmazie, 1997; 52: 57-60), both in vitro, on sixty tumour cell lines in culture, and in vivo, on models of xenografts of human tumour cell lines (colon tumours SW-620 and HTC116, renal tumour A498 and melanoma LOX IM VI) implanted in mice.

Other compounds derived from ascididemin, such as 11-hydroxyascididemin, 11-methoxyascididemin, 11-phenylascididemin, 11-nitrophenylascididemin, 1-nitroascididemin, 3-nitroascididemin and neocalliactine, have been described chemically by various groups, such as those of F. J. Schmitz (J. Org. Chem., 1991; 56: 804-8) and Y. Kitahara et al. (Heterocycles, 1993; 36: 943-46; Tetrahedron Lett., 1997; 53, 17029-38), G. Gellerman et al. (Tetrahedron Lett., 1993; 34: 1827-30), S. Nakahara et al., (Heterocycles, 1993; 36: 1139-44) and I. Spector et al. (U.S. Pat. No. 5,432,172).

Meridine is another natural alkaloid extracted from the ascidian Amphicarpa meridiana or from the marine sponge Corticum sp. Meridine was isolated by F. J. Schmitz et al. (J. Org. Chem., 1991; 56: 804-808) and then described for its antiproliferative properties on a model of murine leukaemia (P388) and its antifungal properties in U.S. Pat. No. 5,182,287 (Gunawardana et al. of 23 Jan. 1993). Its cytotoxic properties on two human cell lines, colon cancer cells (HT-29) and lung carcinoma cells (A549), were reported by R. E. Longley et al. (J. of Nat. Products, 1993; 56: 915-920).

Mention may also be made, among these compounds, of cystodamine, a pentacyclic alkaloid isolated from the ascidian Cystodytes dellechiajei by N. Bontemps et al. (Tetrahedron Lett., 1994; 35: 7023-7026), which exhibits cytotoxic activity with respect to human leukaemia lymphoblasts.

A subject-matter of the present invention is compounds of general formula I and Ia

in which:

R₁, R₂, R₃, R₄ and R₅ are selected from hydrogen, halogens, C₁-C₆ alkyl groups, hydroxyl, —CHO, —OR₈, —COOH, —CN, —CO₂R₈, —CONHR₈, —CONR₈R₉, —NH₂, —NHR₈, —N(R₈)₂, —NH—CH₂—CH₂—N(CH₃)₂, —NH—CH₂—CH₂—Cl, —NHCOR₈, morpholino, nitro, SO₃H,

R₈ and R₉ being selected from C₁-C₆ alkyl groups and phenyl(C₁-C₄)alkyl groups and Ar being a C₆-C₁₄ aryl group,

R₆ is selected from hydrogen, halogens, C₁-C₆ alkyl or —(CH₂)_(n)R₁₀ groups with R₁₀ being selected from halogens or —OH, (C₁-C₆)alkoxy or —O—CO—(C₁-C₆)alkyl groups and n between 1 and 6, —CN, —CO₂Et or —COR₁₁ groups with R₁₁ being selected from C₁-C₆ and phenyl(C₁-C₄)alkyl groups, and —NR₁₂R₁₃ groups with R₁₂ and R₁₃ selected, independently of one another, from hydrogen or C₁-C₆ alkyl, phenyl(C₁-C₄)alkyl or —(CH₂)_(n)R₁₄ groups with R₁₄ being selected from halogens or (C₁-C₆)alkoxy and —N(CH₃)₂ groups and n between 1 and 6,

R—R₇ is selected from hydrogen, groups of type (C₁-C₆)alkyl, phenyl(C₁-C₄)alkyl, —NR₁₅R₁₆ with R₁₅ and R₁₆ selected, independently of one another, from hydrogen, groups of type C₁-C₆ alkyl and phenyl(C₁-C₄)alkyl and —(CH₂)_(n)R₁₇, with R₁₇ selected from hydrogen, halogens or —OH or (C₁-C₆)alkoxy groups and n between 1 and 6,

and the addition salts of these compounds with pharmaceutically acceptable acids.

A specific group of compounds of the formula I and/or Ia is those in which:

R₁, R₂, R₃, R₄ and R₅ are selected from hydrogen, halogens, C₁-C₆ alkyl groups, hydroxyl, —CHO, —OR₈, —COOH, —CN, —CO₂R₈, —CONHR₈, —CONR₈R₉, —NH₂, —NHR₈, —N(R₈)₂, —NH—CH₂—CH₂—N(CH₃)₂, —NHCOR₈, morpholino, nitro, SO₃H,

R₈ and R₉ being selected from C₁-C₆alkyl groups and Ar being a C₆-C₁₄ aryl group.

The subject-matter of the present invention is more particularly the compounds selected from the compounds of formula (I) and of formula (Ia) in which R₁, R₂, R₃, R₄ and R₅ are selected from hydrogen, halogens, C₁-C₆ alkyl groups, hydroxyl, —OR₈, NO₂, —NH₂, —NHR₈, —NH(R₈)₂, —NH—CH₂—CH₂—N(CH₃)₂, —NH—CH₂—CH₂—Cl, —NHCOR₈, R₈ being selected from C₁-C₆ alkyl groups,

R₆ is selected from hydrogen, —(CH₂)_(n)R₁₀ groups, with R₁₀ being selected from halogens, the —O—CO—CH₃ group, C₁-C₆ alkyl groups and N(R₁₂R₁₃) groups with R₁₂ and R₁₃ selected, independently of one another, from hydrogen or C₁-C₆ alkyl, benzyl or —(CH₂)_(n)R₁₄ groups, with R₁₄ being selected from halogens or (C₁-C₆)alkoxy and —N(CH₃)₂ groups and n between 1 and 6,

R₇ selected from hydrogen or groups of type (C₁-C₆)alkyl, benzyl, —N(R₁₅R₁₆) with R₁₅ and R₁₆ selected from hydrogen, groups of type C₁-C₆ alkyl and benzyl, and —(CH₂)_(n)R₁₇, with R₁₇ selected from hydrogen, halogens or —OH or (C₁-C₆)alkoxy groups and n between 1 and 6,

and the addition salts of these compounds with pharmaceutically acceptable acids.

A group of preferred compounds is that composed of the compounds of formula I and Ia in which at least one of the R₁, R₂, R₃, R₄ and R₅ groups is an OR₈ group.

The “addition salts with pharmaceutically acceptable acids” denote the salts which give the biological properties of the free bases without having an undesirable action. These salts can in particular be those formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid or phosphoric acid; metal acid salts, such as disodium orthophosphate and monopotassium sulphate, and organic acids.

Generally, the compounds of formula (I) and (Ia) can be obtained by a process which consists in:

a) reacting, according to a hetero Diels-Alder reaction, a quinolinedione of formula:

 and an azadiene of formula:

where X=CH₃,

in order to obtain a mixture of compounds

b) in optionally separating the compounds of formulae II and IIa,

c₁) subsequently reacting a compound of formulae II and/or IIa with dimethylformamide dimethyl acetal, in order to obtain an enamine of formula:

then functionalizing the enamines, in order to introduce the R₆ and/or R₇ substituents, and cyclizing, in order to obtain the compounds of formulae I and/or Ia,

or

c₂) functionalizing and cyclizing at the same time, in order to obtain the compounds of formulae I and/or Ia,

d) optionally separating the compounds of formulae I and Ia.

In an alternative form, the compounds of formulae I or Ia in which R₆ and R₇ are hydrogens can be obtained by a process which consists in:

a) reacting:

 and an azadiene of formula

where X=CH₂—CH₂—NHBoc,

in order to obtain a mixture of compounds

b) optionally separating the compounds of formulae II and IIa,

c) cyclizing a compound of formulae II and/or IIa, in order to obtain a compound of formulae I and/or Ia,

d) optionally separating the compounds of formulae I or Ia.

The reaction for cyclization of the compounds of formulae III and IIIa can be obtained under hot conditions in the presence of NH₄Cl in an appropriate solvent.

When X=CH₂—CH₂—NHBoc, the compounds of formulae I and Ia are obtained directly in the presence of NaHCO₃ in trifluoroacetic acid medium from the compounds of formulae II and IIa.

The functionalization for the introduction of the R₆ substituent can be obtained with derived reactants, such as R—COCl, ClCN, ClCO₂Et, ClCH₂OR, FClO₃ or CH₂=N⁺ (CH₃)₂I⁻ (in CH₃COOH).

The functionalization for the introduction of an R₇ substituent can be obtained by a Mannich reaction with an aldehyde of formula R₇—CHO.

In this case, the simultaneous cyclization can be obtained in the presence of excess ammonium chloride in acetic acid.

An example of substituted azadiene can be prepared according to the following scheme:

The following examples illustrate the preparation of the compounds of formulae (I) and (Ia).

A—Preparation of the Azadiene (Compound 4)

A-1—Synthesis of N-BOC-1-amino-2-hydroxypropane is (Compound 1)

4.2 g (29.7 mmol) of di-tert-butyl dicarbonate are added at 0° C. to a solution of 2 ml (27 mmol) of 3-amino-1-propanol in a mixture of 60 ml of dioxane, 30 ml of water and 30 ml of 1N NaOH. The reaction mixture is kept stirred at ambient temperature overnight and then it is acidified to pH 1 using concentrated HCl. After several extractions (3 times 50 ml) with ethyl acetate (AcOEt), the organic phases are dried over MgSO₄ and then concentrated on a rotary evaporator to give 4 g of the expected product in the form of a yellow oil.

Yield: 85%.

¹H NMR (CDCl₃): 1.25 (s, 9H); 2.50 (m, 2H); 3.05 (m, 2H); 3.45 (m, 2H); 5.40 (broad s, 1H).

A-2—Synthesis of N-BOC-3-aminopropanal (Compound 2)

18 g (103 mmol) of Compound 1, 1.62 g (10.4 mmol) of TEMPO (tetramethyl-1-piperidinyloxy, free radical), 2.9 g (10.45 mmol) of tetrabutylammonium chloride and 21 g (75.5 mmol) of N-chlorosuccinimide are suspended in 351 ml of NaHCO₃/K₂CO₃ (0.5N/0.05N) and 351 ml of CHCl₃. The reaction mixture is vigorously stirred for 2 hours. The organic phase is separated by settling, dried over MgSO₄ and then concentrated on a rotary evaporator to give the expected aldehyde in the form of a light orange oil.

Yield: 100%

¹H NMR (CDCl₃): 1.35 (s, 9H); 2.44 (d, 2H, J=6.8 Hz); 3.21 (m, 2H); 4.90 (broad s, 1H); 6.04 (dd, 1H, J=8 and 15.6 Hz); 6.74 (td, 1H, J=6.8 and 15.6 Hz); 9.39 (d, 1H, J=8 Hz).

A-3—Synthesis of N-BOC-5-amino-2-penten-1-al (Compound 3)

11 g (66.7 mmol) of Compound 2 and 24.3 g (80 mmol) of formylmethylenetriphenylphosphorane (FMTP) are dissolved in 350 ml of benzene and then the reaction mixture is brought to reflux for 9 hours. After evaporating the solvent on a rotary evaporator, the residue is filtered a first time through silica [(1/1 CHCl₃/heptane) then CHCl₃] to remove the triphenyl-phosphine. A second filtration through silica (8/2 AcOEt/heptane) makes it possible to obtain 3.88 g of Compound 3 in the form of an orange-yellow oil.

Yield: 29%.

¹H NMR (CDCl₃): 1.47 (s, 9H); 2.60 (m, 2H); 3.38 (m, 2H); 4.82 (broad s, 1H); 6.18 (dd, 1H); 6.88 (td, 1H); 9.55 (d, 1H).

A-4—Synthesis of N-BOC-5-amino-2-penten-1-al dimethylhydrazone (Compound 4)

3.88 g (19.5 mmol) of Compound 3 are added at 0° C. to 1.47 ml (19.5 mmol) of dimethylhydrazine and 8 drops of acetic acid in 30 ml of ether. The reaction mixture is left stirring for 10 min and the organic phase is separated by settling and washed with 1N HCl and then with a saturated NaCl solution. After drying over MgSO₄ and evaporating the solvent on a rotary evaporator, 4.4 g of hydrazone (Compound 4) are obtained in the form of an orange-yellow oil.

Yield: 94%.

¹H NMR (CDCl₃): 2.30 (s, 9H); 2.3 (m, 2H); 2.82 (m, 2H); 4.52 (broad s, 1H); 5.70 (td, 1H, J=6.8 and 15.6 Hz); 6.22 (ddd, 1H, J=0.8 and 8.8 and 15.6 Hz); 6.96 (d, 1H, J=8.8 Hz).

¹³C NMR (CDCl₃): 28.15; 33.05; 39.58; 42.51; 78.77; 130.84; 130.95; 135;54; 155.68.

B—Preparation of the Compounds of Formula II and Ia

B-1: Synthesis of 4-methylpyrido[2,3-g]quinoline-5,10-dione (Intermediate I-1b) and of 4-methylpyrido-[3,2-g]quinoline-5,10-dione (Intermediate II-1b)

A mixture of 0.5 g (3.14 mmol) of quinoline-5,8-dione, 0.35 g (3.14 mmol) of crotonaldehyde dimethylhydrazone and 0.45 ml (4.76 mmol) of acetic anhydride in 20 ml of CHCl₃ are treated in an ultrasonic bath for 1 hour. After evaporating the solvent on a rotary evaporator, the reaction mixture is filtered through silica (CHCl₃) to give 0.428 g of a mixture of the two isomers I-1a and II-1a in the form of a purple powder. This powder and 1.6 g (18.4 mmol) of MnO₂ are suspended in 20 ml of CHCl₃ and the mixture is brought to reflux for 2 hours. After filtering through celite, the filtrate is concentrated on a rotary evaporator and then purified by flash chromatography on a silica column (98/2 CH₂Cl₂/MeOH) to give:

Intermediate (I-1b): 4-methylpyrido[2,3-g]quinoline-5,10-dione

40 mg (Yield: 6%) in the form of a brown powder.

Melting point: 220° C.

¹H NMR (CDCl₃): 2.91 (s, 3H); 7.54 (d, 1H, J=4.8 Hz); 7.75 (dd, 1H, J=4 and 7.6 Hz); 8.67 (dd, 1H, J=2 and 7.6 Hz); 8.91 (d, 1H, J=4.8 Hz); 9.12 (dd, 1H, J=2 and 4 Hz).

¹³C NMR (CDCl₃): 22.75; 127.93; 128.04; 129.32; 131.50; 135.50; 148.73; 149.26; 152.11; 153.68; 155.47; 181.46; 182.87.

IR (CHCl₃): 1689 cm⁻¹.

Intermediate (II-1b): 4-methylpyrido[3,2-g]quinoline-5,10-dione

160 mg (Yield: 23%) in the form of a brown powder.

Melting point: 270° C.

¹H NMR (CDCl₃): 2.94 (s, 3H); 7.52 (d, 1H, J=4.8 Hz); 7.76 (dd, 1H, J=4.8 and 8.4 Hz); 8.59 (dd, 1H, J=2 and 8.4 Hz); 8.92 (d, 1H, J=−4.8 Hz); 9.11 (dd, 1H, J=2 and 4.8 Hz).

¹³C NMR (CDCl₃): 22.81; 128.30; 128.39; 130.84; 131.55; 135.52; 147.90; 149.95; 151.74; 153.94; 155.35; 180.42; 184.02.

IR (CHCl₃) 1672; 1700.

B-2: Synthesis of 9-methoxy-4-methylpyrido[2,3-g]quinoline-5,10-dione (Intermediate I-2b) and of 6-methoxy-4-methylpyrido[3,2-g]quinoline-5,10-dione (Intermediate II-2b)

A mixture of 0.5 g (2.8 mmol) of 4-methoxyquinoline-5,8-dione, 0.32 g (2.87 mmol) of crotonaldehyde dimethylhydrazone and 0.4 ml (4.23 mmol) of acetic anhydride in 8 ml of CHCl₃ are brought to reflux for 1 hour. After evaporating the solvent on a rotary evaporator, the reaction mixture is filtered through silica (98/2 CH₂Cl₂/MeOH) to give 0.48 g of a mixture of the two isomers I-2a and II-2a in the form of a purple powder. This powder and 2.3 g (26.45 mmol) of MnO₂ are suspended in 26 ml of CHCl₃ and the mixture is brought to reflux for 2 hours. After filtering through celite, the filtrate is concentrated on a rotary evaporator and then purified by flash chromatography on a silica column (98/2 CH₂Cl₂/MeOH) to give:

Intermediate I-2b: 9-methoxy-4-methylpyrido[2,3-g]quinoline-5,10-dione

57 mg (Yield: 8%) in the form of a red powder.

¹H NMR (CDCl₃): 2.84 (s, 3H); 4.06 (s, 3H); 7.18 (d, 1H, J=6 Hz); 7.46 (d, 1H, J=4.4 Hz); 8.87 (d, 1H, J=6 Hz); 8.87 (d, 1H, J=4.4 Hz).

Intermediate II-2b: 6-methoxy-4-methylpyrido[3,2-g]quinoline-5,10-dione

293 mg (Yield: 40%) in the form of an orange powder.

¹H NMR (CDCl₃): 2.80 (s, 3H); 4.05 (s, 3H); 7.2 (d, 1H, J=6 Hz); 7.48 (d, 1H, J=4.8 Hz); 8.85 (d, 1H, J=6 Hz); 8.88 (d, 1H, J=4.8 Hz).

¹³C NMR (CDCl₃): 21.75; 43.41; 112.74; 119.72; 130.93; 131.04; 148.32; 149.22; 150.26; 151.60; 152.80; 155.11; 181.44; 184.53.

IR (CHCl₃): 1675; 1700 cm⁻¹.

B-3: Synthesis of 9-nitro-4-methylpyrido[2,3-g]quinoline-5,10-dione (Intermediate I-5b) and of 6-nitro-4-methylpyrido[3,2-g]quinoline-5,10-dione (Intermediate II-5b)

A mixture of 0.8 g (3.92 mmol) of 4-nitroquinoline-5,8-dione, 0.65 g (5.8 mmol) of crotonaldehyde dimethylhydrazone and 0.55 ml (5.8 mmol) of acetic anhydride in 10.5 ml of CHCl₃ are treated in an ultrasonic bath for 30 min. After evaporating the solvent on a rotary evaporator, the reaction mixture is filtered through silica (98/2 CH₂Cl₂/MeOH) to give 0.7 g of a mixture of the two isomers I-5a and II-5a in the form of a purple powder. This powder and 2.9 g (33.4 mmol) of MnO₂ are suspended in 29 ml of CHCl₃ and the mixture is brought to reflux for 2 hours. After filtering through celite, the filtrate is concentrated on a rotary evaporator and then purified by flash chromatography on a silica column (98/2 CH₂Cl₂/MeOH) to give:

Intermediate I-5b: 9-nitro-4-methylpyrido[2,3-g]quinoline-5,10-dione

110 mg (Yield: 11%) in the powder form.

¹H NMR (CDCl₃): 2.98 (s, 3H); 7.19 (d, 1H, J=5.6 Hz); 7.54 (d, 1H, J=4.8 Hz); 8.79 (d, 1H, J=5.6 Hz); 8.94 (d, 1H, J=4.8 Hz).

IR (CHCl₃): 1703 cm⁻¹.

Intermediate II-5b: 6-nitro-4-methylpyrido[3,2-g]quinoline-5,10-dione

165 mg (Yield: 16%) in the form of a yellow-brown powder.

¹H NMR (CDCl₃): 2.85 (s, 3H); 7.6 (d, 1H, J=4.8 Hz); 7.74 (d, 1H, J=4.8 Hz); 8.99 (d, 1H, J=4.8 Hz); 9.33 (d, 1H, J=4.8 Hz).

B-4: Synthesis of 9-dimethylamino-4-methylpyrido[2,3-g]quinoline-5,10-dione (Intermediate I-3b) and of 6-dimethylamino-4-methylpyrido[3,2-g]quinoline-5,10-dione (Intermediate II-3b)

150 mg (0.558 mmol) of nitrated tricycle I-5a or II-5a and 0.4 ml (1.95 mmol) of N,N-dimethylformamide diethyl acetal are dissolved in 2.1 ml of DMF and the reaction mixture is heated at 130° C. for 1 hour. After evaporating the solvent with a vacuum pump, 140 mg of intermediate compound II-3a or II-3b are obtained, which material will be used as is in the following stage:

Intermediate II-3b: 6-dimethylamino-4-methylpyrido[3,2-g]quinoline-5,10-dione

Yield: 94%.

¹H NMR (CDCl₃): 2.77 (s, 3H); 3.05 (s, 6H); 6.89 (d, 1H, J=6 Hz); 7.39 (d, 1H, J=4.8 Hz); 8.42 (d, 1H, J=6 Hz); 8.74 (d, 1H, J=4.8 Hz).

B-5: Synthesis of 9-chloro-4-(N-BOC-1-aminoethane)-5,10-dihydropyrido[2,3-g]quinoline-5,10-dione (Intermediate I-7b) and of 6-chloro-4-(N-BOC-1-aminoethane)-5,10-dihydropyrido[3,2-g]quinoline-5,10-dione (Intermediate II-7b)

A mixture of 0.6 g (3.1 mmol) of 4-chloroquinoline-5,8-dione, 0.75 g (3.1 mmol) of dimethylhydrazone 4 and 0.45 ml (4.76 mmol) of acetic anhydride in 8.5 ml of CHCl₃ are treated in an ultrasonic bath for 30 min. After evaporating the solvent on a rotary evaporator, 2.7 g (31.1 mmol) of MnO₂ and 22 ml of CHCl₃ are added to the reaction mixture, which is brought to reflux for 2 hours. After filtering through celite, the filtrate is concentrated on a rotary evaporator and then purified by flash chromatography on a silica column (99/1 CH₂Cl₂/MeOH) to give:

Intermediate I-7b: 9-chloro-4-(N-BOC-1-aminoethane)-5,10-dihydropyrido[2,3-g]quinoline-5,10-dione:

70 mg (Yield: 6%) in the form of a brown powder.

¹H NMR (CDCl₃): 1.35 (s, 9H); 3.45-3.52 (m, 4H); 4.86 (broad s, 1H); 7.56 (d, 1H, J=4.0 Hz); 7.74 (d, 1H, J=5.2 Hz); 8.90 (d, 1H, J=5.2 Hz); 8.94 (d, 1H, J=4 Hz).

¹³C NMR (CDCl₃): 28.37; 35.32; 40.30; 79.47; 126.84; 128.04; 130.88; 131.17; 145.78; 150.34; 150.98; 152.29; 154.05; 154.36; 155.88; 179.76; 182.32.

IR (CHCl₃): 1695 cm⁻¹.

Intermediate II-7b: 6-chloro-4-(N-BOC-1-aminoethane)-5,10-dihydropyrido[3,2-g]quinoline-5,10-dione

200 mg (Yield: 17%) in the form of a brown powder.

¹³C NMR (CDCl₃): 28.24; 34.96; 40.33; 79.47; 128.46; 130.15; 131.06; 131.59; 145.20; 148.76; 149.71; 151.74; 153.88; 153.92; 155.84; 179.76; 183.20.

IR (CHCl₃): 1705 cm⁻¹.

B-6: Synthesis of 3-methoxy-4-methylpyrido[2,3-g]quinoline-5,10-dione (Intermediate I-8b) and of 3-methoxy-4-methylpyrido[3,2-g]quinoline-5,10-dione (Intermediate II-8b)

A mixture of 1 g (6.28 mmol) of quinoline-5,8-dione and 1.78 g (12.57 mmol) of 2-methoxy-2-butenal dimethylhydrazone in 25 ml of CHCl₃ are stirred at ambient temperature for 5 hours. After evaporating the solvent on a rotary evaporator, the reaction mixture is filtered through silica (95/5 CH₂Cl₂/MeOH) to give 1.55 g of a mixture of the two isomers I-8a and II-8a in the form of a purple powder. This powder and 1 g (11.5 mmol) of MnO₂ are suspended in 30 ml of CHCl₃ and the mixture is stirred at ambient temperature for 1 hour. After filtering through celite, the filtrate is concentrated on a rotary evaporator and then purified by flash chromatography on a silica column (99/1 CH₂Cl₂/MeOH) to give:

Intermediate I-8b: 3-methoxy-4-methylpyrido[2,3-g]quinoline-5,10-dione

110 mg (Yield: 7%) in the form of a brown powder.

Melting point: >260° C.

¹H NMR (CDCl₃): 2.79 (s, 3H); 4.11 (s, 3H); 7.72 (dd, 1H, J=4.8 and 8,1 Hz); 8.66 (s, 1H); 8.67 (dd, 1H, J=8.1 and 1.9 Hz); 9.10 (dd, 1H, J=4.8 and 1.9 Hz).

¹³C NMR (CDCl₃): 13.03; 56.87; 127.88; 129.50; 129.95; 135.50; 136.64; 139.26; 142.56; 149.33; 155.11; 157.24; 180.63; 183.56.

IR (CHCl₃): 1684 cm⁻¹.

Intermediate II-8b: 3-methoxy-4-methylpyrido[3,2-g]quinoline-5,10-dione

190 mg (Yield: 12%) in the form of a brown powder.

Melting point: >260° C.

¹H NMR (CDCl₃): 2.77 (s, 3H); 4.12 (s, 3H); 7.74 (dd, 1H, J=4.6 and 8.0 Hz); 8.60 (dd, 1H, J=8.0 and 1.6 Hz); 8.68 (s, 1H); 9.12 (dd, 1H, J=4.6 and 1.6 Hz).

¹³C NMR (CDCl₃): 12.98; 56.93; 127.99; 129.06; 131.27; 135.53; 136.84; 138.81; 143.27; 148.16; 155.20; 157.16; 179.69; 184.59.

IR (CHCl₃): 1670; 1692 cm⁻¹.

B-7: Synthesis of 3,9-dimethoxy-4-methylpyrido[2,3-g]quinoline-5,10-dione (Intermediate I-9b) and of 3,6-dimethoxy-4-methylpyrido[3,2-g]quinoline-5,10-dione (Intermediate II-9b)

A solution of 2-methoxy-2-butenal dimethylhydrazone (1 g, 7.1 mmol) in 15 ml of chloroform is added dropwise to a solution of 4-methoxyquinolinedione (1.33 g, 7 mmol) in 30 ml of chloroform. The reaction mixture is kept stirred at ambient temperature, under nitrogen and with the exclusion of light for 5 hours. After evaporating the solvent on a rotary evaporator, the crude product obtained is purified by flash chromatography through silica (CHCl₃, then 98/2 CHCl₃/MeOH, then 95/5 CHCl₃/MeOH) to produce a first fraction F₁ comprising the nonaromatic product and a second fraction F₂ comprising the expected product. 1 g of MnO₂ is added to the fraction F1 and 30 ml of chloroform. The mixture is left stirring for 90 min. After filtering through celite and washing the precipitate with CHCl₃ and then with MeOH, the filtrate is concentrated on a rotary evaporator to produce a fraction F_(1′). The fractions F_(1′) and F₂ are combined and then purified by flash chromatography through silica (CHCl₃ and then 97/3 CHCl₃/MeOH) to give the two expected compounds I-9a and II-9b in the form of a brown powder.

Intermediate (II-9b): 3,6-dimethoxy-4-methylpyrido[3,2-g]quinoline-5,10-dione

Yield: 11% (210 mg).

Melting point: >260° C.

¹H NMR (CDCl₃): 2.68 (s, 3H) 4.09 (s, 3H); 4.10 (s, 3H); 7.18 (d, 1H, J=5.5 Hz); 8.60 (s, 1H); 8.88 (d, 1H, J=5.5 Hz).

¹³C NMR (CDCl₃): 12.85; 56.81; 56.84; 111.14; 121.32; 130.95; 136,43; 137.79; 141.95; 150.31; 155.44; 157.33; 165.97; 180.13; 184.24.

IR (CHCl₃): 1678, 1692 cm⁻¹.

B-8—Synthesis of 3-methoxy-4-methyl-9-chloropyrido[2,3-g]quinoline-5,10-dione (Intermediate I-10b) and of 3-methoxy-4-methyl-6-chloropyrido[3,2-g]quinoline-5,10-dione (Intermediate II-10b)

A solution of 2-methoxy-2-butenal dimethylhydrazone (1 g, 7.1 mmol) in 15 ml of chloroform is added dropwise to a solution of 4-chloroquinolinedione (1.37 g, 7.1 mmol) in 30 ml of chloroform. The reaction mixture is kept stirred at ambient temperature, under nitrogen and with the exclusion of light, for 5 h 30. After evaporating the solvent on a rotary evaporator, the crude product obtained is purified by flash chromatography through silica (CHCl₃, then 98/2 CHCl₃/MeOH) to produce a first fraction F₁ comprising the nonaromatic product. 1 g of MnO₂ is added to this fraction F₁ and 30 ml of chloroform. The mixture is left stirring at ambient temperature for 60 min. After filtering through celite and washing the precipitate with CHCl₃ and then with MeOH, the mixture is concentrated on a rotary evaporator. The crude product obtained is purified by flash chromatography through silica (97/3 [lacuna]) to give the compounds I-10b and II-10b in the form of a yellow powder.

Intermediate II-10b: 3-methoxy-4-methyl-6-chloropyrido[3,2-g]quinoline-5,10-dione

Yield: 5% (100 mg).

Melting point: >260° C.

¹H NMR (CDCl₃): 2.68 (s, 3H); 4.11 (s, 3H); 7.71 (d, 1H, J=5.2 Hz); 8.64 (s, 1H); 8.90 (d, 1H, J=5.2 Hz).

¹³C NMR (CDCl₃): 12.96; 56.97; 128.92; 130.72; 130.98; 136.95; 138.12; 141.93; 145.06; 150.21; 153.85; 157.55; 179.31; 183.67.

IR (CHCl₃): 1696; 1684 cm⁻¹.

B-9: Synthesis of 3-methoxy-4-methyl-9-dimethylaminopyrido[2,3-g]quinoline-5,10-dione (Intermediate I-11b) and of 3-methoxy-4-methyl-6-dimethylaminopyrido[3,2-g]quinoline-5,1-dione (Intermediate II-11b)

A solution of I-10b or of II-10b (90 mg, 0.31 mmol), of dimethylammonium chloride (127 mg, 1.56 mmol) and of NaOH (63 mg, 1.56 mmol) in a THF/H₂O (4 ml/2 ml) mixture is brought to reflux for 1 hour. After evaporating the solvent on a rotary evaporator, the crude product obtained is taken up in a 95/5 CH₂Cl₂/MeOH mixture (50 ml). The organic phase is recovered and then dried over MgSO₄. After concentrating on a rotary evaporator, the crude product obtained is purified by flash chromatography through silica (95/5 CH₂Cl₂/MeOH) to give the expected compounds I-11b or II-11b in the form of a yellow powder.

Intermediate II-11b: 3-methoxy-4-methyl-6-dimethylaminopyrido[3,2-glguinoline-5,10-dione

Yield: 87% (80 mg).

Melting point: >260° C.

¹H NMR (CDCl₃): 2.64 (s, 3H); 3.06 (s, 6H); 4.08 (s, 3H); 6.95 (d, 1H, J=5.9 Hz); 8.53 (d, 1H, J=5.9 Hz); 8.56 (s, 1H).

¹³C NMR (CDCl₃): 12.62; 43.40; 56.80; 112.39; 120.50; 132.23; 135.90; 136.08; 141.86; 150.53; 151.70; 155.04; 157.19; 180.67; 185.45.

IR (CHCl₃): 1693; 1654 cm⁻¹.

B-10: Synthesis of 3,7-dimethoxy-4-methylpyrido[2,3-g]quinoline-5,10-dione (Intermediate I-12b) and of 3,8-dimethoxy-4-methylpyrido[3,2-g]quinoline-5,10-dione (Intermediate II-12b)

1—Synthesis of 2-methoxyquinoline-5,8-dione

A suspension of 5,8-dioxocarbostyryl (3.1 g, 17.7 mmol), of silver carbonate (10.2 g, 37 mmol) and of methyl iodide (31 ml, 498 mmol) in 1.2 l of CHCl₃ is stirred in the dark at ambient temperature for 90 hours. The precipitate is removed by filtration and the filtrate is concentrated on a rotary evaporator. The crude product obtained is purified by filtration through silica (CHCl₃) to give the expected quinone in the form of a yellow solid (2.2 g).

Yield: 66%).

Melting point: 196° C.

¹H NMR (CDCl₃): 4.14 (s, 3H); 6.95 (d, 1H, J=10.3 Hz); 7.02 (d, 1H, J=10.3 Hz); 7.06 (d, 1H, J=8.8 Hz); 8.25 (d, 1H, J=8.8 Hz).

¹³C NMR (CDCl₃): 54.70; 116.68; 124.32; 136.83; 137.54; 138.21; 146.58; 167.14; 183.48; 184.31.

2—Synthesis of 3,7-dimethoxy-4-methylpyrido[2,3-g]quinoline-5,10-dione (Intermediate I-12b) and of 3,8-dimethoxy-4-methylpyrido[3,2-g]quinoline-5,10-dione (Intermediate II-12b)

A solution of 2-methoxy-2-butanal dimethylhydrazone (0.75 g, 5.3 mmol) in 10 ml of THF is added dropwise to a solution of methoxyquinolinedione (1.0 g, 5.3 mmol) in 60 ml of THF. The reaction mixture is kept stirred at ambient temperature, under nitrogen and with the exclusion of light, for 40 hours. After evaporating the solvent on a rotary evaporator, the crude product obtained is dissolved in 80 ml of CHCl₃ and 85% MnO₂ (5.4 g, 53 mmol) is added. The reaction mixture is kept stirred for 2 hours and is then filtered through celite. After concentrating on a rotary evaporator, the crude product obtained is purified by flash chromatography through silica (CHCl₃) to give the compounds I-12b and II-12b in the form of a brown powder.

Intermediate II-12b: 3,8-dimethoxy-4-methylpyrido[3,2-g]quinoline-5,10-dione

Yield: 8% (120 mg).

Melting point: >260° C.

¹H NMR (CDCl₃): 2.74 (s, 3H); 4.09 (s, 3H); 4.20 (s, 3H); 7.09 (d, 1H, J=8.4 Hz); 8.41 (d, 1H, J=8.4 Hz); 8.63 (s, 1H).

¹³C NMR (CDCl₃):

IR (CHCl₃): 1667, 1693 cm⁻¹.

B-11: Synthesis of 8-ethoxycarbonyl-8-(2′-N-BOC-aminoethyl)pyrido[2,3-g]quinoline-5,10-dione (Intermediate I-13b) and of 7-ethylcarbonyl-6(2′-N-BOC-aminoethyl)pyrido[3,2-g]quinoline 5,10-dione (Intermediate II-13b)

A solution of N-BOC-5-amino-2-penten-1-al dimethylhydrazone (1.1 g, 4.56 mmol) in 15 ml of acetonitrile is added dropwise to a solution of 3-ethylquinolinecarboxylate-5,8-dione (1.05 g, 4.54 mmol) and of acetic anhydride (4.6 ml) in 75 ml of acetonitrile. The reaction mixture is kept stirred at ambient temperature, under nitrogen and with the exclusion of light, for 24 hours. After evaporating the solvent on a rotary evaporator, 5 g of MnO₂ and 150 ml of chloroform are added to the crude product obtained. The mixture is left stirring at ambient temperature for 1 h 30. After filtering through celite and washing the precipitate with CHCl₃ and then with MeOH, the mixture is concentrated on a rotary evaporator. The crude product obtained is purified, first by filtration through silica (99/1 and then 97/3 CH₂Cl₂/MeOH) and then by flash chromatography through silica (99/1), to give the compounds I-13b and II-13b in the form of a brown powder.

Intermediate II-13b: 7-ethoxycarbonyl-6-(2′-N-BOC-aminoethyl)pyrido[3,2-g]quinoline-5,10-dione

Yield: 3% (60 mg).

Melting point: 170° C.

¹H NMR (CDCl₃): 1.36 (s, 9H); 1.47 (t, 3H, J=7.4 Hz); 3.52 (m, 4H); 4.51 (q, 2H, J=7.4 Hz); 4.78 (broad 9, 1H); 7.57 (d, 1H, J=5.2 Hz); 8.99 (d, 1H, J=5.2 Hz); 9.17 (d, 1H, J=2.2 Hz); 9.64 (d, 1H, J=2.2 Hz).

¹³C NMR (CDCl₃): 14.33; 28.40; 35.74; 40.22; 62.62; 79.63; 128.65; 130.33; 130.49; 131.83; 137.30; 149.60; 150.23; 152.72; 154.23; 155.72; 155.98; 163.52; 179.69; 183.38.

IR (CHCl₃): 3457; 1726; 1705; 1677 cm⁻¹.

B-12: Synthesis of 7-hydroxy-4-(2′-N-Boc-aminoethyl)pyrido[2,3-g]quinoline-5,10-dione (Intermediate I-14b) and of 8-hydroxy-4-(2′-N-Boc-aminoethyl)pyrido[3,2-g]quinoline-5,10-dione (Intermediate II-14b)

A solution of N-BOC-5-amino-2-penten-1-al dimethylhydrazone (1.49 g, 6.15 mmol) in 30 ml of acetonitrile is added dropwise to a solution of 5,8-dioxocarbostyril (0.98 g, 5.59 mmol) and of acetic anhydride (5.8 ml) in 100 ml of acetonitrile. The reaction mixture is kept stirred at ambient temperature, under nitrogen and with the exclusion of light, for 16 hours. After evaporating the solvent on a rotary evaporator, 7 g (80.5 mmol) of MnO₂ and 180 ml of chloroform are added to the crude product obtained. The mixture is left stirring at ambient temperature for 1 h 30. After filtering through celite and washing the precipitate with CHCl₃ and with MeOH, the mixture is concentrated on a rotary evaporator. The crude product obtained is purified by filtration through silica (98/2 and then 95/5 CH₂Cl₂/MeOH) to give the compound I-14b and II-14b in the form of a brown powder.

Intermediate II-14b: 8-hydroxy-4-(2′-N-Boc-aminoethyl)pyrido[3,2-g]quinoline-5,10-dione

Yield: 12% (230 mg).

Melting point: 252° C.

¹H NMR (CDCl₃): 1.56 (s, 9H); 3.49 (m, 4H); 4.73 (broad s, 1H); 6.94 (d, 1H, J=9.6 Hz); 7.54 (d, 1H, J=4.8 Hz); 8.10 (d, 1H, J=9.6 Hz); 8.89 (d, 1H, J=4.8 Hz); 9.66 (broad s, 1H).

¹³C NMR (CDCl₃): 28.29; 35.53; 40.24; 117.01; 127.87; 128.62; 132.29; 136.18; 138.04; 148.25; 152.26; 153.33; 155.86; 176.36; 181.35.

IR (CHCl₃): 3457; 3340; 1693; 1663 cm⁻¹.

B-13: Synthesis of 7-hydroxy-4-methylpyrido[2,3-g]quinoline-5,10-dione (Intermediate I-15b) and of 8-hydroxy-4-methylpyrido[3,2-g]quinoline-5,10-dione (Intermediate II-15b)

A solution of 2-butenal dimethylhydrazone (0.703 g, 6.28 mmol) in 20 ml of acetonitrile is added dropwise to a solution of 5,8-dioxocarbostyril (1 g, 5.71 mmol) and of acetic anhydride (6.2 ml) in 220 ml of acetonitrile. The reaction mixture is kept stirred at ambient temperature, under nitrogen and with the exclusion of light, for 16 hours and is then heated at reflux for 6 hours. After evaporating the solvent on a rotary evaporator, the crude product obtained is purified by filtration through silica (CH₂Cl₂ and then 98/2 CH₂Cl₂/MeOH) to produce a first fraction comprising the nonaromatic product and the expected product. 3 g of MnO₂ and 75 ml of chloroform are added to the mixture, which is left stirring at ambient temperature overnight. After filtering through celite and washing the precipitate with CHCl₃ and then with MeOH, the mixture is concentrated on a rotary evaporator. The crude product obtained is purified by flash chromatography through silica (99/1) to give the expected compounds I-15b and II-15b in the form of a beige powder.

Intermediate II-15b: 8-hydroxy-4-methylpyrido[3,2-g]quinoline-5,10-dione

Yield: 12%.

Melting point: >260° C.

¹H NMR (d₆-DMSO): 2.79 (s, 3H); 6.82 (d, 1H, J=9.5 Hz); 7.73 (d, 1H, J=5.2 Hz); 8.05 (d, 1H, J=9.5 Hz); 8.85 (d, 1H, J=5.2 Hz); 12.27 (broad s, 1H).

¹³C NMR (d₆-DMSO): 21.92; 114.30; 122.66; 127.30; 131.52; 135.94; 148.60; 149.80; 152.48 (2C); 176.41; 182.13 (2C).

IR (CHCl₃): 1684; 1664 cm⁻¹.

B-14: Synthesis of 7-methoxy-4-methylpyrido[2,3-g]quinoline-5,10-dione (Intermediate I-16b) and of 8-methoxy-4-methylpyrido[3,2-g]quinoline-5,10-dione (Intermediate II-16b)

A mixture of compound I-15b or II-15b (70 mg, 0.29 mmol), of methyl iodide (1 ml, 15.9 mmol) and of Ag₂CO₂ (170 mg, 0.62 mmol) in 100 ml of CHCl₃ is stirred at ambient temperature and with the exclusion of light for 14 hours and is then heated at 56° C. for 5 hours. After concentrating on a rotary evaporator, the crude product obtained is purified by flash chromatography through silica (99.5/0.5 CH₂Cl₂/MeOH) to give the expected compounds I-16b or II-16b in the form of a beige-brown powder.

Intermediate II-16b: 8-methoxy-4-methylpyrido[3,2-g]quinoline-5,10-dione.

Yield: 41% (30 mg).

Melting point: 128° C.

¹H NMR (CDCl₃): −4.14 (s, 3H); 7.07 (d, 1H, J=8.8 Hz); 7.44 (d, 1H, J=4.8 Hz); 8.37 (d, 1H, J=8.8 Hz); 8.85 (d, 1H, J=4.8 Hz).

¹³C NMR (CDCl₃): 54.92; 117.58; 126.24; 128.09; 131.30; 137.73; 147.31; 150.00; 151.34; 153.38; 167.39; 180.44; 183.70.

IR (CHCl₃): 1765; 1698; 1667; 1603 cm⁻¹.

B-15: Synthesis of 7,9-dichloro-4-methylpyrido[2,3-g]quinoline-5,10-dione (Intermediate I-17b) and of 6,8-dichloro-4-methylpyrido[3,2-g]quinoline-5,10-dione (Intermediate II-17b)

1. Synthesis of 2,4-dichloroquinoline-5,8-dione

Cerium ammonium nitrate (CAN 21.4 g, 39.03 mmol) is added portionwise to a solution of 2,4-dichloro-5,8-dimethoxyquinoline (2.85 g, 11.04 mmol) in a CH₃CN/H₂O mixture (150 ml/75 ml). The reaction mixture is stirred at ambient temperature for 40 min. The acetonitrile is subsequently evaporated and 50 ml of water and 200 ml of a saturated NaHCO₃ solution are added. The aqueous phase is extracted with CH₂Cl₂ (5 times 200 ml). After drying over MgSO₄, the solvent is evaporated on a rotary evaporator to give the expected compound in the form of a brown powder (1.9 g).

Yield: 75%.

Melting point: 161° C.

¹H NMR (CDCl₃): 7.03 (d, 1H, J=10.6 Hz); 7.11 (d, 1H, J=10.6 Hz); 7.74 (s, 1H).

¹³C NMR (CDCl₃): 124.43; 131.10; 136.91; 139.52; 146.69; 148.96; 156.16; 180.53; 182.01.

IR (CHCl₃): 1687; 1676 cm⁻¹.

2. Synthesis of 7,9-dichloro-4-methylpyrido[2,3-g]quinoline-5,10-dione (Intermediate I-17b) and of 6,8-dichloro-4-methylpyrido[3,2-g]quinoline-5,10-dione (Intermediate II-17b)

A solution of 2-butenal dimethylhydazone (0.325 g, 2.89 mmol) in 20 ml of acetonitrile is added dropwise to a solution of 2,4-dichloroquinoline-5,8-dione (0.6 g, 2.63 mmol) and of acetic anhydride (5 ml) in 100 ml of acetonitrile. The reaction mixture is kept stirred at ambient temperature, under nitrogen and with the exclusion of light, for 20 hours. After evaporating the solvent on a rotary evaporator, the crude product obtained is taken up in 140 ml of CHCl₃. 3.65 g of MnO₂ are subsequently added and then the mixture is left stirring at ambient temperature for 56 hours. After filtering through celite and washing the precipitate with CHCl₃ and then with MeOH, the solution is concentrated on a rotary evaporator. The crude product obtained is purified by flash chromatography through silica (CH₂Cl₂) to give the expected compounds I-17b and II-17b in the form of a brown powder.

Intermediate II-17b: 6,8-dichloro-4-methylpyrido[3,2-g]quinoline-5,10-dione

Yield: 41% (314 mg).

Melting point: 177° C.

¹H NMR (CDCl₃): 2.87 (s, 3); 7.56 (d, 1H, J=4.8 Hz); 7.79 (s, 1H); 8.93 (d, 1H, J=4.8 Hz).

¹³C NMR (CDCl₃): 22.41; 125.44; 127.84; 131.13; 131.30; 147.44; 149.81; 150.62; 151.90; 154.30; 156.58; 179.12; 180.66.

IR (CHCl₃): 1706; 1683 cm⁻¹.

B-16—Synthesis of 7,9-dimethoxy-4-methylpyrido[2,3-g]quinoline-5,10-dione (Intermediate 1-18b) and of 6,8-dimethoxy-4-methylpyrido[3,2-g]quinoline-5,10-dione (Intermediate II-18b)

A mixture of compound I-17b or of compound II-17b (80 mg, 0.27 mmol) and of sodium methoxide (300 mg of Na in 40 ml of methanol, 13.04 mmol) in 40 ml of methanol is brought to ref lux for 17 hours. The reaction mixture is concentrated to dryness and then 50 ml of water are added. After neutralizing with 25% HCl, the solution is extracted with CH₂Cl₂ (3 times 50 ml). After drying over MgSO₄ and evaporating the solvent on a rotary evaporator, the expected compounds I-18b or II-18b [lacuna] quantitatively.

Intermediate II-18b: 6,8-dimethoxy-4-methylpyrido[3,2-g]quinoline-5,10-dione

Melting point: 219° C.

¹H NNR (CDCl₃): 2.88 (s, 1H); 4.03 (s, 3H); 4.07 (s, 3H); 6.53 (s, 1H); 7.45 (d, 1H, J=4.8 Hz); 8.83 (d, 1H, J=4.8 Hz).

¹³C NMR (CDCl₃): 22.64; 54.73; 56.80; 97.79; 117.61; 129.55; 131.46; 148.67; 149.41; 150.73; 152.96; 167.95; 168.00; 180.91; 183.41.

IR (CHCl₃): 1701; 1668 cm⁻¹.

EXAMPLE 1 7H-Pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8293) and 7-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8294)

63 mg (2.81 mmol) of compound I-b and 1.7 ml (9.84 mmol) of dimethylformamide diethyl acetal in 4.5 ml of DMF are brought to 120° C., under nitrogen, for 1 hour. After evaporating the solvent with a vacuum pump, 3.5 g (65 mmol) of NH₄Cl and 60 ml of absolute ethanol are added. The reaction mixture is brought to reflux for 30 min. After evaporating the ethanol on a rotary evaporator, 50 ml of water are added to the residue and extraction is carried out with CH₂Cl₂ (3 times 50 ml). After drying the organic phases over MgSO₄ and evaporating the solvent on a rotary evaporator, 0.6 g of CRL 8294 are obtained in the form of a greenish powder.

7H-Pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8293)

Yield: 90%.

Melting point: 240° C.

¹H NMR (CDCl₃): 7.68 (dd, 1H, J=4.4 and 8 Hz); 7.87 (d, 1H, J=5.6 Hz); 8.02 (d, 1H, J=5.2 Hz); 8.77 (dd, 1H, J=1.6 and 8 Hz); 9.11 (d, 1H, J=5.2 Hz); 9.16 (dd, 1H, J=1.6 and 4.4 Hz); 9.19 (d, 1H, J=5.6 Hz).

¹³C NMR (CDCl₃): 120.95; 124.40; 126.14; 129.32; 136.78; 139.09; 147.45; 148.58; 148.82; 148.96; 150.66; 152.00; 155.73; 181.96.

7H-Pyrido[4,3,2-de][1,7phenanthroline-7-one (CRL 8294)

By following the procedure described above starting from the intermediate II-1b, 72 mg of compound CRL 8294 are obtained in the form of a yellow powder.

Yield: 80%.

¹H NMR (CDCl₃): 7.76 (dd, 1H, J=4.4 and 8 Hz); 7.80 (d, 1H, J=5.2 Hz); 7.99 (d, 1H, J=5.6 Hz); 8.93 (d, 1H, J=5.6 Hz); 9.05 (dd, 1H, J=1.6 and 4.4 Hz); 9.17 (dd, 1H, J=1.6 and 8 Hz); 9.19 (d, 1H, J=5.2 Hz)

¹³C NMR (CDCl₃): 119.39; 120.01; 123.85; 128.15; 132.87; 133.80; 138.65; 147.54; 147.74; 148.93; 149.49; 149.99; 152.97; 180.73.

EXAMPLE 2 8-Methoxy-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8363) and 11-methoxy-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8364)

74 mg (2.92 mmol) of compound I-2b and 2 ml (11.8 mmol) of dimethylformamide diethyl acetal in 5.2 ml of DMF are brought to 120° C., under nitrogen, for 1 hour. After evaporating the solvent with a vacuum pump, 4.5 g (83.6 mmol) of NH₄Cl and 67 ml of absolute ethanol are added. The reaction mixture is brought to reflux for 30 min. After evaporating the ethanol on a rotary evaporator, 50 ml of water are added to the residue and extraction is carried out with CH₂Cl₂ (3 times 50 ml). After drying the organic phases over MgSO₄ and evaporating the solvent on a rotary evaporator, the residue is purified by flash chromatography on a silica column (98/2 CHCl₃/MeOH) to give 0.28 g of compound CRL 8363 in the form of an orange powder.

8-Methoxy-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8363)

Yield: 37%.

¹H NMR (CDCl₃): 4.20 (s, 3H); 7.13 (d, 1H, J=5.6 Hz); 7.82 (d, 1H, J=5.2 Hz); 7.94 (d, 1H, J=6 Hz); 8.92 (d, 1H, J=5.6 Hz); 9.07 (d, 1H, J=6 Hz); 9.13 (d, 1H, J=5.2 Hz); 9.19 (d, 1H, J=5.2 Hz).

¹³C NMR (CDCl₃): 56.77; 109.26; 119.70; 120.47; 123.09; 138.50; 147.85; 148.25; 148.69; 150.66; 154.08; 155.68; 167.54; 180.40.

11-Methoxy-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8364)

By following the procedure described above starting from 1.14 g of the intermediate II-2b, 0.59 g of compound CRL 8364 are obtained in the form of a yellow powder.

Yield: 50%.

¹H NMR (CDCl₃): 4.15 (s, 3H); 7.26 (d, 1H, J=6 Hz); 7.70 (d, 1H, J=6 Hz); 7.96 (d, 1H, J=5.6 Hz); 8.85 (d, 1H, J=6 Hz); 8.97 (d, 1H, J=6 Hz); 9.15 (d, 1H, J=5.6 Hz).

¹³C NMR (CDCl₃): 57.05; 111.33; 118.72; 119.61; 122.12; 124.29; 138.56; 146.71; 147.10; 148.69; 149.81; 150.96; 153.13; 165.83; 180.82.

EXAMPLE 3 8-(Dimethylamino)-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8800) and 11-(dimethylamino)-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8367)

80 mg (0.3 mmol) of tricycle I-3b or of tricycle II-3b and 0.21 ml (1.05 mmol) of dimethylformamide diethyl acetal in 1.2 ml of DMF are brought to 120° C., under nitrogen, for 1 hour. After evaporating the solvent with a vacuum pump, 0.5 g (9.3 mmol) of NH₄Cl and 80 ml of absolute ethanol are added. The reaction mixture is brought to reflux for 40 min. After evaporating the ethanol on a rotary evaporator, 5 ml of water are added to the residue and extraction is carried out with CH₂Cl₂ (3 times 5 ml). After drying the organic phases over MgSO₄ and evaporating the solvent on a rotary evaporator, the two tetracyclic compounds are obtained quantitatively in the form of a red powder.

11-(Dimethylamino)-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8367)

¹H NMR (CDCl₃): 3.00 (s, 6H); 7.09 (d, 1H, J=5.2 Hz); 7.57 (d, 1H, J=5.6 Hz); 7.90 (d, 1H, J=5.2 Hz); 8.54 (d, 1H, J=5.2 Hz); 8.89 (d, 1H, J=5.2 Hz); 9.11 (d, 1H, J=5.6 Hz).

EXAMPLE 4 8-Hydroxy-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8802) and 11-hydroxy-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8388)

50 mg (0.126 mmol) of tricycle I-7b or of tricycle II-7b are dissolved in 0.5 ml of TFA and then the reaction mixture is stirred for 24 hours. The TFA is evaporated on a rotary evaporator and then a saturated NaHCO₃ solution is added until a pH of 9-10 is obtained. The mixture is extracted with CH₂Cl₂ (3 times 3 ml). After drying over MgSO₄ and evaporating the solvent on a rotary evaporator, 20 mg of tetracyclic compound are obtained in the form of a yellow powder.

11-Hydroxy-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8388)

Yield: 62%.

Melting point: >260° C.

¹H NMR (CDCl₃): 7.20 (d, 1H, J=5.6 Hz); 7.83 (d, 1H, J=6 Hz); 8.00 (d, 1H, J=6 Hz); 8.72 (d, 1H, J=6 Hz); 8.76 (d, 1H, J=6 Hz); 9.24 (d, be 1H, J=5.6 Hz), 14.65 (s, 1H).

¹³C NMR (d₆-DMSO): 116.22; 116.35; 118.61; 120.24; 124.06; 138.09; 143.61; 148.04; 148.99; 149.41; 152.61; 153.01; 165.80; 179.55.

EXAMPLE 5 8-Chloro-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8396) and 11-chloro-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8801)

260 mg (0.67 mmol) of tricycle I-7b or of tricycle II-7b are dissolved in 2.6 ml of TFA and then the reaction mixture is stirred for 64 hours. The TFA is evaporated on a rotary evaporator and then 200 ml of 95/5 CH₂Cl₂/MeOH are added, followed by a saturated NaHCO₃ solution until a pH of 10 is obtained. The organic phase is recovered and is washed with water. After drying over MgSO₄ and evaporating the solvent on a rotary evaporator, 40 mg of tetracyclic compounds are obtained in the form of a brown powder which is washed with ether.

8-Chloro-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8396)

Yield: 28%.

Melting point: >260° C.

¹H NMR (CDCl₃): 7.68 (d, 1H, J=5.2 Hz); 7.89 (d, 1H, J=5.5 Hz); 8.01 (d, 1H, J=5.5 Hz); 8.96 (d, 1H, J=5.2 Hz); 9.14 (d, 1H, J=5.5 Hz); 9.19 (d, 1H, J=5.5 Hz).

¹³C NMR (d₆-DMSO): 119.87; 120.88; 123.61; 126.31; 129.01; 138.56; 146.87; 147.37; 148.46; 148.94; 149.76; 153.85; 153.96; 179.87.

EXAMPLE 6 4-Methoxy-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8400) and 4-methoxy-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8401)

100 mg (0.39 mmol) of tricycle I-8b or of tricycle II-8b and 0.27 ml (1.37 mmol) of dimethylformamide diethyl acetal in 0.7 ml of DMF are brought to 120° C., under nitrogen, for 1 hour. After evaporating the solvent with a vacuum pump, 0.6 g (11.7 mmol) of NH₄Cl and 90 ml of absolute ethanol are added. The reaction mixture is brought to reflux for 30 min. After evaporating the ethanol on a rotary evaporator, 10 ml of water are added to the residue and extraction is carried out with CH₂Cl₂ (3 times 10 ml). After drying the organic phases over MgSO₄, evaporating the solvent on a rotary evaporator and purifying by filtration through silica (95/5 CH₂Cl₂/MeOH), the compounds CRL 8400 and CRl 8401 are obtained in the form of a brown powder.

4-Methoxy-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8400)

Yield: 83% (85 mg).

Melting point: >260° C.

¹H NMR (CDCl₃): 4.27 (s, 3H); 7.65 (dd, 1H, J=4.8 and 8 Hz); 8.15 (d, 1H, J=6 Hz); 8.70 (s, 1H); 8.78 (dd, 1H, J=8 and 1.9 Hz); 9.10 (d, 1H, J=6 Hz); 9.13 (dd, 1H, J=1.9 and 4.8 Hz).

¹³C NMR (d₆-DMSO): 56.97; 115.63; 120.81; 125.52; 129.02; 129.16; 130.22; 136.24; 139.81; 147.37; 149.31; 151.65; 153.07; 154.81; 180.34.

IR (CHCl₃): 1674 cm⁻¹.

4-Methoxy-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8401)

Yield: 59%.

Melting point: >260° C.

¹H NMR (CDCl₃): 4.27 (s, 3H); 7.74 (dd, 1H, J=4.4 and 8.1 Hz); 8.08 (d, 1H, J=5.6 Hz); 8.72 (s, 1H); 8.93 (d, 1H, J=5.6 Hz); 9.05 (dd, 1H, J=1.9 and 4.4 Hz); 9.19 (dd, 1H, J=1.9 and 8.1 Hz).

¹³C NMR (d₆-DMSO): 57.03; 115.16; 119.70; 127.69; 129.48; 130.15; 132.86; 133.74; 140.82; 146.80; 147.98; 148.63; 152.81; 152.98; 179.84.

IR (CHCl₃): 1679 cm⁻¹.

EXAMPLE 7 4,8-Dimethoxy-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8803) and 4,11-dimethoxy-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8440)

A solution of the compound I-9b or of the compound II-9b (100 mg, 0.35 mmol) and of N,N-dimethylformamide diethyl acetal (0.24 ml, 1.23 mmol) in 1 ml of DMF is brought to 120° C. for 90 min. The reaction mixture is concentrated under high vacuum to remove the DMF and the residue is diluted in 100 ml of absolute EtOH. After adding 0.6 g of NH₄Cl, the mixture is brought to reflux for 30 min. After concentrating on a rotary evaporator, 30 ml of water are added and the mixture is extracted with CHCl₃ (3 times 75 ml). The organic phases are dried over MgSO₄ and concentrated. The crude product obtained is purified by flash chromatography through silica (95/5 CHCl₃/MeOH) to give the compounds in the form of a yellow powder.

4,11-Dimethoxy-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8440)

Yield: 26% (27 mg).

Melting point: >260° C.

¹H NMR (d₆-DMSO): 4.08 (s, 3H); 4.26 (s, 3H); 7.54 (d, 1H, J=5.9 Hz); 7.98 (d, 1H, 5.9 Hz); 8.77 (d, 1H, J=5.9 Hz); 8.83 (s, 1H); 8.94 (d, 1H, J=5.9 Hz).

¹³C NMR (d₆-DMSO): 57.41; 58.07; 112.43; 113.75; 119.84; 122.13; 129.60; 130.54; 140.17; 146.81; 150.17; 150.62; 153.03; 153.35; 166.06; 179.30.

IR (CHCl₃): 1682; 1608; 1572 cm⁻¹.

MS: m/z 293 (34); 292 (42); 220 (19); 192 (30); 165 (22).

EXAMPLE 8 4-Methoxy-8-dimethylamino-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8804) and 4-methoxy-11dimethylamino-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8441)

A solution of the compound I-11b or of the compound II-11b (80 mg, 0.27 mmol) and of N,N-dimethylformamide diethyl acetal (0.18 ml, 0.94 mmol) in 2 ml of DMF is brought to 120° C. for 3 hours. The reaction mixture is concentrated under high vacuum to remove the DMF and the residue is diluted in 90 ml of absolute EtOH. After adding 0.4 g of NH₄Cl, the mixture is brought to reflux for 30 min and then concentrated on a rotary evaporator. 30 ml of water are added and then the solution is extracted with CH₂Cl₂ (3 times 50 ml). The organic phases are dried over MgSO₄ and concentrated. The crude product obtained is purified by flash chromatography through silica (95/5 CH₂Cl₂/MeOH) to give the tetracyclic compounds in the form of a red-brown powder.

4-Methoxy-11-dimethylamino-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8441)

Yield: 40% (33 mg).

Melting point: decomposes.

¹H NMR (CDCl₃): 3.02 (s, 6H); 4.23 (s, 3H); 7.08 (d, 1H, J=5.9 Hz); 7.87 (d, 1H, J=5.5 Hz); 8.54 (d, 1H, J=5.9 Hz); 8.65 (s, 1H); 8.90 (d, 1H, J=5.5 Hz).

¹³C NMR (CDCl₃): 44.28; 56.94; 112.14; 113.63; 119.38; 119.73; 129.31; 129.99; 140.20; 145.81; 150.31; 150.63; 151.41; 152.99; 156.77; 180.57.

IR (CHCl₃): 1682 cm⁻¹.

MS: m/z 306 (52); 305 (32); 291 (100); 290 (66); 276 (24); 248 (9); 220 (13); 193 (21).

EXAMPLE 9 4,10-Dimethoxy-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8805) and 4,9-dimethoxy-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8479)

A solution of the compound I-12b or of compound II-12b (100 mg, 0.35 mmol) and of N,N-dimethylformamide diethyl acetal (0.24 ml, 1.23 mmol) in 1 ml of DMF is brought to 120° C. for 1 hour. The reaction mixture is concentrated under high vacuum to remove the DMF and the residue is diluted in 100 ml of absolute EtOH. After adding 0.54 g of NH₄Cl, the mixture is brought to reflux for 30 min. After concentrating on a rotary evaporator, 20 ml of water are added and the solution is extracted with CHCl₃ (3 times 30 ml). The organic phases are dried over MgSO₄ and concentrated. The crude product obtained is purified by flash chromatography through silica (CHCl₃) to give the tetracyclic compounds in the form of a green powder.

4,9-Dimethoxy-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8479)

Yield: 36% (37 mg).

Melting point: >260° C.

¹H NMR (d₆-DMSO): 4.21 (s, 3H); 4.24 (s, 3H); 7.16 (d, 1H, J=8.8 Hz); 7.98 (d, 1H, 5.6 Hz); 8.69 (s, 1H); 8.85 (d, 1H, J=5.6 Hz); 9.00 (d, 1H, J=8.8 Hz).

¹³C NMR (d₆-DMSO): 54.44; 56.92; 114.04; 117.17; 118.86; 127.74; 129.43; 129.99; 136.29; 141.16; 146.36; 146.72; 149.38; 152.94; 165.80; 179.70.

IR (CHCl₃): 1679 cm⁻¹.

MS: m/z 293 (44); 248 (100); 220 (12).

EXAMPLE 10 9-Ethoxycarbonyl-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8805) and 10-ethoxycarbonyl-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8482)

A solution of the compound I-13b or of the compound II-13b (30 mg, 0.07 mmol) and of trifluoroacetic acid (0.27 ml, 3.5 mmol) in 15 ml of CH₂Cl₂ is stirred for 64 hours. After concentrating on a rotary evaporator, the reaction mixture is basified with 10 ml of saturated NaHCO₃ solution and extracted with CHCl₃ (2 times 30 ml). The organic phases are dried over MgSO₄ and then concentrated on a rotary evaporator. The residue obtained is purified by filtration through silica to give the tetracyclic compounds in the form of a yellow powder.

10-Ethoxycarbonyl-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8482)

Yield: 53% (11.3 mg).

Melting point: 246° C.

¹H NMR (CDCl₃): 1.49 (t, 3H, J=7.3 Hz); 4.53 (q, 2H, J=7.3 Hz); 7.85 (d, 1H, J=5.9 Hz); 8.03 (d, 1H, J=5.5 Hz); 8.98 (d, 1H, J=5.9 Hz); 9.22 (d, 1H, J=5.5 Hz); 9.56 (d, 1H, J=1.9 Hz); 9.73 (d, 1H, J=1.9 Hz).

¹³C NMR (CDCl₃): 14.32; 62.29; 119.61; 120.39; 124.04; 129.94; 132.60; 135.46; 138.77; 147.78; 149.17; 149.46; 153.23; 164.15; 180.20 (1C not observed).

IR (CHCl₃): 1726; 1694 cm⁻¹.

MS: m/z 305 (92); 260 (7); 232 (93); 204 (25).

EXAMPLE 11

10-Hydroxy-7H-pyrido[4,3,2-de][1,0]phenanthroline-7-one (CRL 8809) and 9-hydroxy-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8483)

A solution of the compound I-14b or of the compound II-14b (tricycle 56) (50 mg, 0.135 mmol) and of trifluoroacetic acid (0.54 ml, 7 mmol) in 30 ml of CH₂Cl₂ is stirred for 48 hours. After concentrating on a rotary evaporator, the reaction mixture is basified with 13 ml of saturated NaHCO₃ solution and extracted with CH₂Cl₂ (7 times 30 ml). The organic phases are dried over MgSO₄ and then concentrated on a rotary evaporator. The residue obtained is purified by flash chromatography (97/2 CH₂Cl₂/MeOH) to give the tetracyclic compounds in the form of an orange powder.

9-Hydroxy-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8483)

Yield: 50% (16.8 mg).

Melting point: >260° C.

¹H NMR (CDCl₃): 7.06 (d, 1H, J=9.5 Hz); 7.72 (d, 1H, J=5.9 Hz); 8.02 (d, 1H, J=5.2 Hz); 8.70 (d, 1H, J=9.5 Hz); 8.87 (d, 1H, J=5.9 Hz); 9.19 (d, 1H, J=5.5 Hz).

IR (CHCl₃): 1690; 1667; 1602 cm⁻¹.

MS: m/z 249 (100); 221 (77.6); 193 (99.2).

EXAMPLE 12 10-Methoxy-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8810) and 9-methoxy-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8484)

A solution of the compound I-16b or of the compound II-16b (200 mg, 0.786 mmol) and of N,N-dimethylformamide diethyl acetal (0.47 ml, 2.73 mmol) in 3.2 ml of DMF is brought to reflux for 2 hours. The reaction mixture is concentrated under high vacuum to remove the DMF and the residue is diluted in 200 ml of absolute EtOH. After adding 1.4 g of NH₄Cl (26.2 mmol), the solution is brought to reflux for 30 min. After concentrating on a rotary evaporator, 50 ml of water are added and then the solution is extracted with CH₂Cl₂ (5 times 40 ml). The organic phases are dried over MgSO₄ and concentrated. The crude product obtained is purified by flash chromatography through silica (99/1 CH₂Cl₂/MeOH) to give the tetracyclic compounds in the form of a brown powder.

9-Methoxy-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8484)

Yield: 10% (20 mg).

Melting point: >260° C.

¹H NMR (CDCl₃): 4.14 (s, 3H); 7.11 (d, 1H, J=8.8 Hz); 7.63 (d, 1H, J=5.5 Hz); 7.87 (d, 1H, J=5.5 Hz); 8.77 (d, 1H, J=5.5 Hz); 8.91 (d, 1H, J=8.8 Hz); 9.09 (d, 1H, J=5.5 Hz).

¹³C NMR (CDCl₃): 53.41; 117.66; 118.54; 118.93; 123.70; 127.73; 136.29; 138.52; 145.95; 147.45; 148.03; 148.83; 150.19; 165.86; 180.55.

IR (CHCl₃): 1686 cm⁻¹.

MS: m/z 263 (8.2); 233 (25.1); 204 (35.4).

EXAMPLE 13 8,10-Dimethoxy-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8811) and 9,11-dimethoxy-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8485)

A solution of the compound I-18b or of the compound II-18b (105 mg, 0.37 mmol) and of N,N-dimethylformamide diethyl acetal (0.22 ml, 1.29 mmol) in 1.5 ml of DMF is brought to reflux for 1 h 30. The reaction mixture is concentrated under high vacuum to remove the DMF and then the residue is diluted in 95 ml of absolute EtOH. 0.7 g of NH₄Cl (13.08 mmol) is added and the solution is brought to reflux for 30 min. After concentrating on a rotary evaporator, 50 ml of water are added. The solution is extracted with CH₂Cl₂ (5 times 40 ml). The organic phases are dried over MgSO₄ and concentrated. The crude product obtained is purified by flash chromatography through silica (99/1 CH₂Cl₂/MeOH) to give the tetracyclic compounds in the form of an orange-yellow powder.

9,11-Dimethoxy-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8485)

Yield: 9% (10 mg).

Melting point: >260° C.

¹H NMR (CDCl₃): 4.12 (s, 3H); 4.18 (s, 3H); 6.65 (s, 1H); 7.64 (d, 1H; J=5.5 Hz); 7.92 (d, 1H, J=5.5 Hz); 8.93 (d, 1H, J=5.5 Hz); 9.14 (d, 1H, J=5.5 Hz).

¹³C NMR (CDCl₃): 54.39; 57.02; 98.26; 117.89; 118.64; 118.86; 124.16; 138.50; 146.93; 147.09; 148.29; 148.62; 151.50; 166.32; 167.73; 180.65.

IR (CHCl₃): 1688 cm⁻¹.

MS: m/z 293 (15); 292 (28); 233 (24); 204 (13); 165 (10).

EXAMPLE 14 8-Dimethylamino-10-chloro-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8812) and 9-chloro-11-dimethylamino-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8485)

A solution of the compound I-17b or of the compound II-17b (110 mg, 0.375 mmol) and of N,N-dimethylformamide diethyl acetal (0.23 ml, 1.31 mmol) in 1.1 ml of DMF is brought to reflux for 1 h 30. The reaction mixture is concentrated under high vacuum to remove the DMF and then the residue is diluted in 95 ml of absolute EtOH. After adding 0.7 g of NH₄Cl (13.08 mmol), the mixture is brought to reflux for 30 min. and then concentrated on a rotary evaporator. 50 ml of water are added and then the solution is extracted with CH₂Cl₂ (5 times 40 ml). The organic phases are dried over MgSO₄ and concentrated. The crude product obtained is purified by flash chromatography through silica (99/1 CH₂Cl₂/MeOH) to give the tetracyclic compounds in the form of a purple-red powder.

9-Chloro-11-dimethylamino-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8486)

Yield: 3% (3.3 mg).

Melting point: 246° C.

¹H NMR (CDCl₃): 3.04 (s, 6H); 7.11 (s, 1H); 7.61 (d, 1H, J=5.5 Hz); 7.92 (d, 1H, J=5.5 Hz); 8.90 (d, 1H, J=5.5 Hz); 9.14 (d, 1H, J=5.5 Hz).

¹³C NMR (CDCl₃): 44.39; 113.57; 117.60; 119.00; 119.37; 123.99; 138.50; 146.51; 146.77; 148.83; 150.68; 150.89; 153.68; 158.21; 180.05.

IR (CHCl₃): 1698 cm⁻¹.

MS: m/z 311 (19); 309 (11); 296 (89); 294 (100); 269 (4); 267 (1); 204 (66).

EXAMPLE 15 4-Hydroxy-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one dihydroiodide (CRL 8813) and 4-hydroxy-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one dihydroiodide, (CRL 8487)

Hydriodic acid (57% in water: 10 ml, 44.6 mmol) is added to a suspension of compound CRL 8400 or of compound CRL 8401 (50 mg, 0.19 mmol) in acetic acid (4 ml). The mixture is heated at 100° C. for 21 hours. After cooling and then filtering, the dihydroiodide of the expected compounds is isolated in the form of a purple powder.

4-Hydroxy-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one dihydroiodide (CRL 8487)

Yield: 85% (82 mg).

Melting point: >260° C.

¹H NMR (d₆-DMSO): 6.75 (d, 1H, J=5.8 Hz); 7.42 (broad s, 1H); 7.63 (dd, 1H, J=8.4 and 4.4 Hz); 8.20 (d, 1H, J=5.8 Hz); 9.07 (m, 2H).

IR (CHCl₃): 3037; 1647; 1635; 1617; 1604 cm⁻¹.

EXAMPLE 16 4-Chloro-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8806) and 4-chloro-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8480)

A solution of compound CRL 8813 or of compound CRL 8487 (45 mg, 0.14 mmol) in POCl₃ (3.5 ml) is brought to reflux for 2 hours. After evaporating on a rotary evaporator, the mixture is basified to pH 8 with a 1N NaHCO₃ solution (10 ml) and then extraction is carried out with a 5% MeOH/CHCl₃ mixture (2×20 ml). The organic phases are dried over MgSO₄ and then concentrated on a rotary evaporator. The residue obtained is purified by flash chromatography (99/1 CH₂Cl₂/MeOH) to give the expected compounds in the form of a brown powder.

4-Chloro-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8480)

Yield: 4% (2 mg).

Melting point: >260° C.

¹H NMR (CDCl₃): 7.78 (dd, 1H, J=4.4 and 8.1 Hz); 8.08 (d, 1H, 5.9 Hz); 9.03 (d, 1H, J=5.9 Hz); 9.07 (dd, 1H, J=4.4 and 1.8 Hz); 9.18 (s, 1H); 9.19 (dd, 1H, J=1.8 and 8.1 Hz).

¹³C NMR (CDCl₃): 116.63; 119.80; 128.25; 132.64; 134.05; 137.03; 145.92; 147.56; 147.78 (2C); 148.47; 149.93; 153.31; 180.08.

IR (CHCl₃): 1692; 1608 cm⁻¹.

MS: m/z 269 (34), 267 (100), 232 (60); 204 (29).

EXAMPLE 17 4-Dimethylamino-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8807) and 4-dimethylamino-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8481)

A solution of compound CRL 8806 or of compound CRL 8480 (14 mg, 0.052 mmol) of dimethylamine hydrochloride (24 mg, 0.29 mmol) and of sodium hydroxide (13 mg, 0.32 mmol) in a THF/H₂O mixture (2 ml/1 ml) is brought to reflux for 1 h 30. After concentrating on a rotary evaporator, the mixture is taken up in 15 ml of water. After extracting with CHCl₃ (3×20 ml), the organic phases are dried over MgSO₄ and then concentrated on a rotary evaporator. The residue obtained is purified by flash chromatography (95/5 CHCl₃/MeOH) to give the expected compounds in the form of a red powder.

4-Dimethylamino-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8481)

Yield: 63% (9 mg).

Melting point; >260° C.

¹H NMR (CDCl₃): 3.34 (s, 6H); 7.71 (dd, 1H, J=4.4 and 8.1 Hz); 7.96 (d, 1H, 6.0 Hz); 8.62 (s, 1H); 8.83 (d, 1H, J=6.0 Hz); 9.04 (dd, 1H, J=1.5 and 4.4 Hz); 9.19 (dd, 1H, J=1.5 and 8.1 Hz).

¹³C NMR (CDCl₃): 44.06 (2C); 117.89; 120.40; 127.22; 129.69; 132.59; 133.68; 135.30; 138.51; 144.67; 146.98; 148.14; 149.16; 152.66; 179.55.

IR (CHCl₃): 1666 cm⁻¹.

MS: m/z 276 (100); 249 (11); 204 (1).

EXAMPLE 18 3-Acetoxymethyl-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8825) and 3-acetoxymethyl-7H-pyrido[4,3,2-de]]1,7]phenanthroline-7-one (CRL 8824)

A solution of the compound I-1b and of compound II-1b (0.11 g, 0.5 mmol) and of dimethylformamide diethyl acetal (1.5 mmol) in DMF (3 ml) is heated under nitrogen at 120° C. for 1 h. After cooling, the mixture is concentrated under vacuum to produce the expected derivative in the solid form. The preceding solid derivative (125 mg, 0.45 mmol) is taken up in DMF and 13 mg (0.7 mmol) of Eschenmoser's salt is added. The mixture is heated under nitrogen at 115° C. for 30 minutes. After cooling, NH₄Cl (10 mmol) and acetic acid (75 ml) are added to the mixture, which is brought to 115° C. for 30 minutes. After cooling, the reaction mixture is poured into ice, basified with 10% KOH and extracted with CHCl₃. The organic phases are dried over MgSO₄ and concentrated on a rotary evaporator. The residue is purified by flash chromatography through silica.

3-Acetal-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8815) and 3-acetal-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8814),

3-cyano-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8817) and 3-cyano-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8816),

3-ethoxycarbonyl-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8819) and 3-ethoxycarbonyl-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8818)

3-methoxymethyl-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8821) and 3-methoxymethyl-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8820)

3-fluoro-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8823) and 3-fluoro-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8822)

3-acetoxymethyl-9-methoxy-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8825) and 3-acetoxymethyl-9-methoxy-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8824),

are prepared according to the procedure described above.

EXAMPLE 19 2-Methyl-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8827) and 2-methyl-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8826)

A mixture of compound I-1b and of compound II-b (80 mg, 0.4 mmol) is dissolved in acetic acid (10 ml) with ammonium chloride (64 mg, 12 mmol) and the solution, kept stirred, is heated to 70° C. Acetaldehyde (88 mg, 2 mmol) in acetic acid (10 ml) is added dropwise. The mixture is heated at reflux under nitrogen for 45 minutes and then cooled. After adding water, the solution is basified with NH₄OH and extracted with dichloromethane. After drying on MgSO₄ and evaporating, the residue obtained is purified by flash chromatography through silica.

2-Benzyl-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8829) and 2-benzyl-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8828),

2-(2′-chloroethyl)-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8831) and 2-(2′-chloroethyl)-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one (CRL 8830),

2-(2′-methoxymethyl)-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8833) and 2-(2′-methoxymethyl)-7H-pyrido[4,3,2-de][1,7]phenanthroline 7-one (CRL 8832),

are prepared according to the procedure described above.

The results of the in vitro and in vivo pharmacological tests, presented below, demonstrate the cytotoxic properties of the compounds of formula (I) and (Ia) and the maximum tolerated doses (MTD).

1—Cytotoxic Activity on Tumour Cell Lines in Culture (MTT Test)

The influence of the compounds of formula (I) and of (Ia) on tumour cells was evaluated using the MTT calorimetric test (T. Mosman, J. Immunol. Methods, 1983; 65: 55-63, J. Carmichael et al., Cancer Res. 1987; 47: 936-942).

The principle of the MTT test is based on the mitochondrial reduction by metabolically active alive cells of the yellow-coloured product MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) to a blue-coloured product, formazan. The amount of formazan thus obtained is directly proportional to the amount of live cells present in the culture well or wells. This amount of formazan is measured by spectrophotometry.

The cell lines are maintained in monolayer culture at 37° C. in stoppered culture dishes containing 25 MM HEPES MEM (Minimum Essential Medium) base medium. This medium is well suited to the growth of a range of varied diploid or primary mammalian cells. This medium is subsequently supplemented:

with an amount of 5% of FCS (Foetal Calf Serum) decomplemented at 56° C. for 1 hour,

with 0.6 mg/ml of L-glutamine,

with 200 IU/ml of penicillin,

with 200 μg/ml of streptomycin,

with 0.1 mg/ml of gentamicin.

The 12 human cancer cell lines which were used were obtained from the American Type Culture Collection (ATCC, Rockville, Md., USA). These 12 cell lines are:

U-373MG (ATCC code: HTB-17) and U-87MG (ATCC code: HTB-14), which are two glioblastomas,

SW1088 (ATCC code: HTB-12) which is an astrocytoma,

A549 (ATCC code: CCL-185) and A-427 (ATCC code: HTB-53), which are two non-small-cell lung cancers,

HCT-15 (ATCC code: CCL-225) and LoVo (ATCC code: CCL-229), which are two colorectal cancers,

T-47D (ATCC code: HTB-133) and MCF7 (ATCC code: HTB-22), which are two breast cancers,

J82 (ATCC code: HTB-1) and T24 (ATCC code: HPB-4), which are two bladder cancers,

PC-3 (ATCC code: CRL-1435), which is a prostate cancer.

Experimentally: 100 μl of a cell suspension comprising 20 000 to 50 000 (depending on the cell type used) cells/ml of culture medium are inoculated in flat-bottomed 96-well multi-well plates and are incubated at 37° C. under an atmosphere comprising 5% of CO₂ and 70% humidity. After incubating for 24 hours, the culture medium is replaced with 100 μl of fresh medium comprising either the various test compounds at concentrations varying from 10⁻⁵ to 10⁻¹⁰ M of the solvent used to dissolve the -test products (control condition). After incubating for 72 hours under the above conditions, the culture medium is replaced with 100 μl of a yellowish solution of MTT dissolved, in a proportion of 1 mg/ml, in RPMI 1640. The microplates are reincubated for 3 hours at 37° C. and then centrifuged for 10 minutes at 400 g. The yellowish MTT solution is removed and the blue formazan crystals formed at the cellular level are dissolved in 100 μl of DMSO. The microplates are subsequently agitated for 5 minutes. The intensity of the resulting blue coloration, and thus of the conversion of the yellow MTT product into blue formazan by the cells which are still alive at the end of the experiment, is quantified by spectrophotometry using a device of DYNATECH IMOASSAY SYSTEM type at wavelengths of 570 nm and 630 nm corresponding respectively to the maximum absorption wavelengths of formazan and to the background noise. Software built into the spectrophotometer calculates the mean optical density values and the standard deviation (Std. Dev.) and standard error of the mean (SEM) values.

The inhibitory activity on the cell growth of the compounds of formula (I) and (Ia) on the various tumour cell lines was measured in comparison with that of the natural product. By way of example, the values of the concentrations framing the 50% inhibitory concentrations (IC₅₀) obtained for each compound are presented in Table I below:

All of the compounds studied exhibit significant inhibitory activity on the cell proliferation of the 12 human tumour lines: U-87MG, U-373MG, SW1088, T24, J82, HCT-15, LoVo, MCF7, T-47D, A549, A-427 and PC-3, with an IC₅₀ which can be between 10⁻⁵ and 10⁻⁹ M, depending on the compounds and the tumour lines tested.

2—Determination of the Maximum Tolerated Dose (MTD)

The evaluation of the maximum tolerated dose was carried out on B6D2F1/Jico mice aged from 4 to 6 weeks. The compounds were administered intraperitoneally at increasing doses ranging from 2.5 to 160 mg/kg. The value of the MTD (expressed in mg/kg) is determined from the observation of the survival rates of the animals over a period of 14 days after a single administration of the product under consideration. The change in the weight of the animals is also monitored over this period. When that the value of the MTD is greater than 160 mg/kg, the value of the MTD is categorized as 160 mg/kg by default.

The results of the assessment of the maximum tolerated dose (MTD) are collated in the following Table II:

TABLE 2 Maximum Tolerated Doses CRL Compounds DMT (mg/kg) CRL 8388 (Example 4)  10 CRL 8293 (Example 1)  10 CRL 8294 (Example 1)  10 CRL 8363 (Example 2)  10 CRL 8364 (Example 2)   5 CRL 8367 (Example 3)  10 CRL 8396 (Example 5)  20 CRL 8400 (Example 6) >160 CRL 8401 (Example 6) >160 CRL 8440 (Example 7)  20 CRL 8441 (Example 8) >160

The products of this family exhibit either a degree of direct toxicity or may be devoid of it and may then be used in vivo at high tissue concentrations and therefore at high dosages.

3—In Vivo Antitumour Activity

The tests were carried out on models of:

hormone-insensitive mouse mammary carcinoma MXT (HI-MXT),

hormone-sensitive mouse mammary adenocarcinoma MXT (HS-MXT),

lymphoma L 1210.

The model of mouse mammary adenocarcinoma MXT of Watson C. et al. (Cancer Res., 1977; 3-7: 3344-48), grafted onto B6D2F1/Jico mice aged from 4 to 6 weeks, is derived from the mammary gland milk ducts. Initially hormone-sensitive (HS-MXT model), the differentiated tumour develops in the direction of an undifferentiated hormone-insensitive tumour (HI-MXT model). The agents with the antitumour activity which has been demonstrated clinically prolong the survival of the animals carrying HI-MXT tumours and HS-MXT tumours. This is the case, for example, with cyclophosphamide, etoposide or adriamycin.

The model of lymophoma L 1210 is a model of L 1210 leukemia cells of mouse origin grafted subcutaneously in the mouse. They give rise, in 100% of cases, to a rapid-growth subcutaneous solid tumour (L 1210 s.c.).

When the MTD value of a product was determined, its in vivo antitumour activity was characterized at the MTD/2, MTD/4 and MTD/8 doses on the models of mammary adenocarcinoma of mouse origin HS-MXT and of mouse mammary carcinoma HI-MXT and on the model of subcutaneous lymphoma L 1210.

In all the examples presented below, whatever the model, the control condition is represented by a batch of 9 or 15 mice to which is administered, for 3 consecutive weeks and at the rate of 3 administrations (Monday, Wednesday and Friday) per week, a volume of 0.2 ml of physiological saline comprising the solvent used to dissolve the various compounds of formula (I) and (Ia) used.

During these tests, either the tumour growth or the survival rate of the mice were determined:

i)—The tumour growth was evaluated by measuring twice weekly (Monday and Friday) the area of the grafted HS-MXT, HI-MXT or L 1210 tumours. This area is calculated by multiplying the value of the two greatest perpendicular axes of the tumour. The value of these axes is measured using a sliding caliper.

ii)—The survival rate of the mice is calculated in the form or a ratio T/C, where: $T = {\begin{matrix} \text{(Number~~of~~days} \\ \text{of~~survival~~of} \\ \text{the~~median~~mouse} \\ \text{of~~the~~batch~~of} \\ \text{mice treated)} \end{matrix} + \frac{\begin{matrix} \text{(Median} \\ \text{mouse} \\ \text{treated)} \end{matrix} - \begin{matrix} \text{(Number~~of~~dead} \\ \text{mice~~in~~the~~days} \\ \text{which~~preceded~~that} \\ \text{of~~the~~median~~mouse} \\ \text{treated)} \end{matrix}}{\begin{matrix} \text{(Number~~of~~dead~~mice~~on~~the~~same} \\ \text{day~~as~~the~~median~~mouse~~treated)} \end{matrix}}}$ $C = {\begin{matrix} \text{(Number~~of~~days} \\ \text{of~~survival~~of} \\ \text{the~~median~~mouse} \\ \text{of~~the~~batch~~of} \\ \text{mice~~treated)} \end{matrix} + \frac{\begin{matrix} \text{(Median} \\ \text{mouse} \\ \text{treated)} \end{matrix} - \begin{matrix} \text{(Number~~of~~dead} \\ \text{mice~~in~~the~~days} \\ \text{which~~preceded~~that} \\ \text{of~~the~~median~~mouse} \\ \text{treated)} \end{matrix}}{\begin{matrix} \text{(Number~~of~~dead~~mice~~on~~the~~same} \\ \text{day~~as~~the~~median~~mouse)} \end{matrix}}}$

This ratio represents the mean survival time of the mean mouse of the batch of treated mice with respect to the mean survival time of the median mouse of the batch of control mice. Thus, a molecule induces a significant (P<0.05) increase in the survival of the animals when the T/C index exceeds 130%. On the other hand, it has a toxic effect when this T/C value is less than 70%.

3.1.—Mouse Mammary Carcinoma (HI-MXT)

The influence of the two products CRL 8293 and CRL 8294 on the growth of HI-MXT tumours will be presented below by way of example. Each batch of mice grafted with HI-MXT tumours relating to a given experimental condition comprises 15 animals.

Treatment 1

The product CRL 8293 is administered intraperitoneally. The first injection of the product is carried out on the seventh day postgrafting (D7) at the rate of the seventh day postgrafting (D7) at the rate of 3 injections per week (Monday, Wednesday and Friday) for 3 consecutive weeks and at a dose of 5 mg/kg.

Treatment 2

The product CRL 8294 is administered intraperitoneally. The first injection of the product is carried out on the seventh day postgrafting (D7) at the rate of 3 injections per week (Monday, Wednesday and Friday) for 3 consecutive weeks and at a dose of 5 mg/kg.

The decreases (−) or the increases (+) in the area of the HI-MXT tumours induced with treatments 1 and 2 with respect to the control condition on the 21st day after the tumour grafting, i.e. after 6 administrations of the product CRL 8293 or of the product CRL 8294, are shown, as percentage, in the following Table II. 100% of the control animals are still alive on the 21st day postgrafting.

TABLE III Tumour area Treatments (expressed as %) 1 (CRL 8293) −33 2 (CRL 8294) −36

These results show that these two products CRL 8293 and CRL 8294 induce a significant decrease in the growth of the HI-MXT tumours. These results show that these products of formula I and Ia exhibit, in vivo and on this model, an advantageous antitumour activity.

3.2.—Mouse Mammary Adenocarcinoma (HS-MXT)

The influence of the two products CRL 8293 and CRL 8294 on the growth of HS-MXT tumours will be presented below by way of example. Each batch of mice grafted with the HS-MXT tumours relating to a given experimental condition comprises 9 animals.

Treatment 10

The product CRL 8293 is administered intraperitoneally. The first injection of the product is carried out on the seventh day postgrafting (D7) at the rate of 3 injections per week (Monday, Wednesday and Friday) for 3 consecutive weeks and at a dose of 5 mg/kg.

Treatment 20

The product CRL 8294 is administered alone by the intraperitoneal route. The first injection of the product is carried out on the seventh day postgrafting (D7) at the rate of 3 injections per week (Monday, Wednesday and Friday) for 3 consecutive weeks and at a dose of 5 mg/kg.

The decreases (−) or the increases (+) in the area of the HS-MXT tumours induced with treatments 10 and 20 with respect to the control condition on the 31st day after the tumour grafting, i.e. after the 9 administrations provided in the experimental protocol of the 2 products CRL 8293 and CRL 8294, are shown, as percentage, in the following Table IV. 100% of the control animals are still alive on the 31st day postgrafting.

TABLE IV Tumour area Treatments (expressed as %) 10 (CRL 8293) −45 20 (CRL 8294) −64

These results show that these two products CRL 8293 and CRL 8294 induce a very highly significant decrease in the growth of the HS-MXT tumours. These results show, as on the HI-MXT model, that the products of formula I and Ia also exhibit on the HS-MXT model a highly advantageous antitumour activity.

3.3.—Lymphoma L 1210

The influence of CRL 8294 on the survival time of the mice will be presented below by way of example (Table V). Each batch of mice grafted with the lymphoma L 1210 relating to a given experimental condition comprises 9 animals.

Treatment 100

The product CRL 8294 is administered alone intraperitoneally. The first injection of the product is carried out on the seventh day postgrafting (D7) at the rate of 3 injections per week (Monday, Wednesday and Friday) for 3 consecutive weeks and at a dose of 1.25 mg/kg.

TABLE V Treatment T/C (expressed a %) 100 (CRL 8294) 136

The compound CRL 8294 of formula (I) exhibits an antitumour activity on the model of subcutaneous lymphoma L 1210. This activity is characterized by a significant extension of the mean survival time of the median mouse of the batch of mice thus treated with respect to the mean survival time of the median mouse of the batch of control mice.

4—Tolerance/cytotoxic activity ratios

The results of the mean IC₅₀ values (in nM) (calculated from the individual cytotoxic activities obtained on each of the 12 tumour lines studied) and the MTD/IC₅₀ ratios, calculated by taking the ratio of the MTD values to the IC₅₀ values, are presented in the following Table VI. The MTD/IC₅₀ ratio is expressed as a dimensionless number.

TABLE VI CRL Compounds IC₅₀ (nM) MTD/IC₅₀ MTD/IC₅₀* CRL 8388 (Example 4) 6200 0.0016 1 CRL 8293 (Example 1) 1250 0.008 5 CRL 8294 (Example 1) 1450 0.007 4.4 CRL 8363 (Example 2)  500 0.02 12.5 CRL 8364 (Example 2)  270 0.019 12 CRL 8367 (Example 3) 1650 0.006 3.8 CRL 8396 (Example 5)  600 0.033 20.6 CRL 8400 (Example 6)  380 0.42 262 CRL 8401 (Example 6)  53 3 1870 CRL 8440 (Example 7)  10 0.42 1240 CRL 8441 (Example 8) 5000 3 19.8 *the MTD/IC₅₀ ratio of the various compounds was evaluated by taking, as reference, a ratio equal to 1 for CRL 8388.

The compounds of formula (I) and (Ia) exhibit significant antitumour activity both in vitro and in vivo under the experimental conditions described above. They inhibit, in vitro, the growth of tumour cells, as indicated by the results of the MTT calorimetric tests. They significantly and greatly inhibit, in vivo, the growth of HI-MXT and HS-MXT tumours and significantly increase the mean survival time of the median mouse of the batch of mice thus treated and grafted with lymphoma L 1210 with respect to the mean survival time of the median mouse of the batch of control mice.

By virtue of their cytotoxic properties, the compounds of formulae (I) and (Ia), as described or in the form of acceptable pharmaceutical salts or solvates, can be used as active principles of medicaments for treating cancerous tumours and their metastases.

The compounds of formulae (I) and (Ia) are generally administered in dosage units drawn up either per m² of body surface or per kg of weight. The said dosage units are preferably formulated in pharmaceutical compositions in which the active principle is mixed with one (or more) pharmaceutical excipient(s).

The compounds of formula (I) and (Ia) can be used, according to the cancer pathology of the subject to be treated, at doses of between 0.05 and 350 mg/m² of body surface, preferably at doses of 0.5 to 50 mg/m²/day for the curative treatment in its acute phase, as a function of the number of treatment cycles of each cure. For a maintenance treatment, the compounds of formulae (I) and (Ia) will advantageously be used at doses of 0.05 to 25 mg/m²/day, preferably at doses of 0.1 to 1.5 mg/m²/day, according to the number of treatment cycles of the cure. They may be used in combination with antitumour medicaments used in protocols validated for intensive polychemotherapy.

In the pharmaceutical compositions of the present invention for oral or intravenous administration, the active principles can be administered in unit administration forms, as a mixture with conventional pharmaceutical vehicles suitable for human therapeutics. The appropriate unit administration forms comprise forms to be taken orally, such as tablets, which may optionally be scored, or gelatin capsules, implants and intravenous administration forms.

For parenteral administration (intravenous infusion at a constant flow rate), use is made of sterile aqueous suspensions, sterile isotonic saline solutions or sterile and injectable solutions which comprise pharmacologically compatible dispersing agents and/or solubilizing agents, for example propylene glycol, polyethylene glycol or a β-cyclodextrin.

Thus, to prepare an aqueous solution for intravenous injection intended for an infusion carried out over 1 to 24 h, use may be made of a cosolvent: an alcohol, such as ethanol, or a glycol, such as polyethylene glycol or propylene glycol, and a hydrophilic surfactant, such as Tween 80.

When a solid composition in the form of tablets is prepared, a wetting agent, such as sodium lauryl sulphate, can be added to the micronized or unmicronized active principle, and the entire combination is mixed with a pharmaceutical vehicle, such as silica, gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, with various polymers or with other appropriate materials while alternatively they can be treated so that they have a sustained or delayed activity and so that they continuously release a predetermined amount of active principle.

The preparation as gelatin capsules is obtained by mixing the active principle with a diluent, such as a glycol or a glycerol ester, and incorporating the mixture obtained in soft or hard gelatin capsules.

The active principle can also be formulated in the form of microcapsules or microspheres, optionally with one or more supports or additives.

The active principle can also be presented in the form of a complex with a cyclodextrin, for example α-, β- or γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin or methyl-β-cyclodextrin.

The compound of formulae (I) and (Ia) will be used in the treatment of the majority of solid tumours as a result of their powerful cytotoxic activities, in particular for treating cerebral tumours, lung cancers, ovarian and breast tumours, endometrium cancers, colorectal cancers, prostate cancers and testicular tumours. 

What is claimed is:
 1. Compounds of formulae:

in which: R₁, R₂, R₃, R₄ and R₅ are selected from hydrogen, halogens, C₁-C₆ alkyl groups, hydroxyl, —CHO, —OR₈, —COOH, —CN, —CO₂R₈, —CONHR₈, —CONR₈R₉, —NH₂, —NHR₈, —N(R₈)₂, —NH—CH₂—CH₂—N(CH₃)₂, —NH—CH₂—CH₂—Cl, —NHCOR₈, morpholino, nitro, SO₃H,

R₈ and R₉ being selected from C₁-C₆ alkyl groups and phenyl(C₁-C₄)alkyl groups and Ar being a C₆-C₁₄ aryl group, R₆ is selected from hydrogen, halogens, C₁-C₆ alkyl or —(CH₂)_(n)R₁₀ groups with R₁₀ being selected from halogens or —OH, (C1-C6)alkoxy or —O—CO—(C₁-C₆)alkyl groups and n between 1 and 6, —CN, —CO₂Et or —COR₁₁ groups with R₁₁ being selected from C₁-C₆ and phenyl(C₁-C₄)alkyl groups, and —NR₁₂R₁₃ groups with R₁₂ and R₁₃ selected, independently of one another, from hydrogen or C₁-C₆ alkyl, phenyl(C₁-C₄)alkyl or —(CH₂)_(n)R₁₄ groups with R₁₄ being selected from halogens or (C₁-C₆)alkoxy and —N(CH₃)₂ groups and n between 1 and 6, R₇ is selected from hydrogen, (C₁-C₆)alkyl, phenyl (C₁-C₄)alkyl, —NR₁₅R₁₆ with R₁₅ and R₁₆ selected, independently of one another, from hydrogen, C₁-C₆ alkyl and phenyl(C₁-C₄)alkyl and —(CH₂)_(n)R₁₇, with R₁₇ selected from hydrogen, halogens or —OH or (C₁-C₆)alkoxy groups and n between 1 and 6, and the addition salts of these compounds with pharmaceutically acceptable acids.
 2. Compounds according to claim 1, which are compounds of formulae I or Ia in which: R₁, R₂, R₃, R₄ and R₅ are selected from hydrogen, halogens, C₁-C₆ alkyl groups, hydroxyl, —CHO, —OR₈, —COOH, —CN, —CO₂R₈, —CONHR₈, —CONR₈R₉, —NH₂, —NHR₈, —N(R₈)₂, —NH—CH₂—CH₂—N(CH₃)₂, —NHCOR₈, morpholino, nitro, SO₃H,

R₈ and R₉ being selected from C₁-C₆ alkyl groups and Ar being a C₆-C₁₄ aryl group.
 3. Compounds according to claim 1, which are compounds of formulae I or Ia in which: R₁, R₂, R₃, R₄ and R₅ are selected from hydrogen, halogens, C₁-C₆ alkyl groups, hydroxyl, —OR₈, NO₂, —NH₂, —NHR₈, —NH(R₈)₂, —NH—CH₂—CH₂—N(CH₃)₂, —NH—CH₂CH₂—Cl, —NHCOR₈, R₈ being selected from C₁-C₆ alkyl groups, R₆ is selected from hydrogen, —(CH₂)_(n)R₁₀ groups, with R₁₀ being selected from halogens, the —O—CO—CH₃ group, C₁-C₆ alkyl groups and NR₁₂R₁₃ groups with R₁₂ and R₁₃ selected, independently of one another, from hydrogen or C₁-C₆ alkyl, benzyl or —(CH₂)_(n)R₁₄ groups, with R₁₄ being selected from halogens or (C₁-C₆)alkoxy and —N(CH₃)₂ groups and n between 1 and 6, R₇ selected from hydrogen or (C₁-C₆)alkyl, benzyl, —NR₁₅R₁₆ with R₁₅ and R₁₆ selected from hydrogen, C₁-C₆ alkyl and benzyl, and —(CH₂)_(n)R₁₇, with R₁₇ selected from hydrogen, halogens or —OH or (C₁-C₆)alkoxy groups and n between 1 and 6, and the addition of salts of these compounds with pharmaceutically acceptable acids.
 4. Compounds according to claim 3, which are compounds of formulae I or Ia in which at least one of the R₁, R₂, R₃, R₄ and R₅ groups is an OR₈ group.
 5. Compounds according to claim 3, which are compounds of formulae I or Ia in which: R₁ is selected from hydrogen, halogens or hydroxyl, methoxy, nitro, —NH₂, —NHCH₃, —NH—CH₂—CH₂—N(CH₃)₂, —NH—CH₂—CH₂—Cl or —NHCOCH₃ groups, R₂ is hydrogen, R₃ and R₅ are selected from hydrogen or hydroxyl or methoxy groups and the addition salts of these compounds with pharmaceutically acceptable acids.
 6. Compounds according to claim 3, which are compounds of formula (I): 11-methoxy-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one, 11-chloro-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one, 4-methoxy-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one, 4,11-dimethoxy-7H-pyrido[4,3,2-de][1,7]-phenanthroline-7-one, 4,9-dimethoxy-7H-pyrido[4,3,2-de][1,7]-phenanthroline-7-one, 9-methoxy-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one, 9,11-dimethoxy-7H-pyrido[4,3,2-de][1,7]-phenanthroline-7-one, 3-acetoxymethyl-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one, 3-acetoxymethyl-9-methoxy-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one, 2-(2-chloroethyl)-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one, and the addition salts of these compounds with pharmaceutically acceptable acids.
 7. Compounds according to claim 3, which are compounds of formula (Ia): 8-methoxy-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one, 8-chloro-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one, 4-methoxy-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one, 4,8-dimethoxy-7H-pyrido[4,3,2-de][1,10]-phenanthroline-7-one, 4,10-dimethoxy-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one, 10-methoxy-7H-pyrido[4,3,2-de][1,10]-phenanthroline-7-one, 8,10-dimethoxy-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one, 3-acetoxymethyl-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one, 3-acetoxymethyl-9-methoxy-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one, 2-(2-chloroethyl)-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one, and the addition salts of these compounds with pharmaceutically acceptable acids.
 8. Pharmaceutical composition comprising an effective amount of a compound selected from the compounds according to claim 1 for treating, by virtue of their cytotoxic properties, cancerous tumours and their metastases.
 9. Process for the preparation of compounds according to claim 1, which consists in: a) reacting, according to a hetero Diels-Alder reaction, a quinolinedione of formula:

 and an azadiene of formula

where X=CH₃, in order to obtain a mixture of compounds

b) optionally separating the compounds of formulae II and IIa, c₁) subsequently reacting a compound of formulae II and or IIa with dimethylformamide dimethyl acetal, in order to obtain an enamine of formula:

then functionalizing the enamines, in order to introduce the R₆ and/or R₇ substituents, and cyclizing, in order to obtain the compounds of formulae I and/or Ia, or c₂) functionalizing and cyclizing at the same time, in order to obtain the compounds of formulae I and/or Ia, d) optionally separating the compounds of formulae I and Ia.
 10. Process for the preparation of compounds according to claim 1 of formulae I or Ia in which and R₇ are hydrogen atoms, which consists: a) in reacting, according to a hetero Diels-Alder reaction, a quinolinedione of formula:

 and an azadiene of formula

where X=CH₂—CH₂—NHBoc, wherein Boc corresponds to tert-butoxycarbonyl, in order to obtain a mixture of compounds

b) optionally separating the compounds of formulae II and IIa, c) cyclizing a compound of formulae II and/or IIa, in order to obtain a compound of formulae I and/or Ia, d) optionally separating the compounds of formulae I or Ia.
 11. Enamine of formula:

in which: R₁, R₂, R₃, R₄ and R₅ are selected from hydrogen, halogens, C₁-C₆ alkyl groups, hydroxyl, —CHO, —OR₈, —COOH, —CN, —CO₂R₈, —CONHR₈, —CONR₈R₉, —NH₂, —NHR₈, —N(R₈)₂, —NH—CH₂—CH₂—N(CH₃)₂, —NH—CH₂—CH₂—Cl, —NHCOR₈, morpholino, nitro, SO₃H,

R₈ and R₉ being selected from C₁-C₆ alkyl groups and phenyl(C₁-C₄)alkyl groups and Ar being a C₆-C₁₄ aryl group.
 12. A method for treating a solid tumour in a patient, which consists in administering, to said patient, an effective amount of a compound according to claim 1, and wherein said solid tumour are selected from the group consisting of cerebral tumours, lung cancers, ovarian tumours, breast tumours, endometrium cancers, colorectal cancers, prostate cancers, testicular tumours, glioblastomas, astrocytomas, non-small-cell lung cancers, bladder cancers, carcinomas and adeno carcinomas.
 13. A method for treating a solid tumour in a patient, comprising administering to said patient an effective amount of a compound according to claim 1, and wherein said solid tumour is selected from the group consisting of cerebral tumours, lung cancers, ovarian tumours, breast tumours, endometrium cancers, colorectal cancers, prostate cancers, testicular tumours, glioblastomas, astrocytomas, non-cell-lung cancers, bladder cancers, carcinomas and adeno carcinomas. 